Virginia Commonwealth University

NSF Awards · FY 2024 · 2024-10

Researchers in higher education seeking to understand challenges to broadening participation in STEM disciplines have generally focused on a few key areas such as visibility and representation, campus climate issues, and institutional policies and support mechanisms. This project seeks to enrich the STEM education enterprise’s understanding of the breadth of backgrounds and experiences of undergraduate STEM majors by filling crucial gaps in the literature. Namely, this study will take an intentionally expansive approach, analyzing the ways that multiple factors might overlap and intersect to shape the experiences and academic outcomes of students with multiple interlocking backgrounds. Additionally, this study will employ a methodological framework that seeks to address some of the shortcomings of standard quantitative approaches by explicitly incorporating variables related to individuals’ experiences and backgrounds into statistical modeling. Finally, the study will intentionally oversample groups that have been historically understudied to address the dearth of data on such groups. As a result, the proposed study will generate new knowledge about undergraduates that is multi-dimensional, quantitative, and inclusive of a broad set of student characteristics and backgrounds. The results of this study hold promise to help inform future programming, interventions, policies, and practices that can improve the experiences, retention, and representation of all students pursuing courses of study in STEM fields. The proposed work consists of two components: a systematic literature review and a quantitative study. The systematic literature review contributes to the project in two ways. First, there is no existing systematic literature review of the research on undergraduate STEM student engagement, performance, and persistence that offers a comprehensive consideration of a fine-grained characterization of the different dimensions of student identity. This review will serve as a crucial resource in furthering work in this area. Secondly, the review will also include coding for theoretical perspectives engaged, how and whether demographic data were considered, the inclusion of data reflecting the rich diversity of student experiences and identities, analytic methods, and other substantive findings or results. The second phase of the project is a quantitative study that will seek to generate new insights, using a variety of methods that are rooted in and ask questions that reflect the different experiences of undergraduate majors in STEM. The project will bring together this broad set of theoretical perspectives and new quantitative methodologies emerging from the study of the relationships between social conceptions of race and ethnicity, social constructs and political laws, and the continually evolving media landscape. The sampling procedure will oversample students in groups historically underrepresented and underacknowledged in their participation in STEM to account for their underrepresentation in the literature and to support robust analyses. Planned analyses include latent profile analysis, chi-square tests to follow up on patterns in profile membership, and multilevel modeling to test for patterns of differences across identity categories and majors. This work will be guided by a group of established experts in STEM education and more educational research representing a breadth of lived experience and methodological expertise. The study will contribute to the field by expanding quantitative methodologies to integrate person-centered methodologies that recognize fluidity and instability and improve the measurement of identity categories. The project is supported by NSF’s EDU Core Research Building Capacity in STEM Education Research (ECR: BCSER) program, which is designed to build investigators’ capacity to carry out high-quality STEM education research. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-10

The implementation of active learning approaches in STEM undergraduate courses has significantly increased over the past few decades. Classrooms traditionally dominated by lectures have been reworked into environments where students actively participate in discussions, problem-solving, group work, and hands-on projects. Improvement in students' overall academic achievement in these environments has consistently been reported, but researchers have found that some students encounter barriers that significantly limit their participation and impact their learning experiences in these courses. Understanding these obstacles and how these students interact with peers and instructors in small-group settings is crucial for developing more effective educational practices. Despite this need, no rigorous studies have yet examined these interactions in undergraduate mathematics classrooms. Addressing this research gap is crucial for the STEM curriculum, considering the pivotal role these courses play in the STEM pipeline and their strong impact on student retention in STEM disciplines. This project will use surveys, interviews, and classroom observations to conduct a thorough analysis of the interactions among students working in small groups in undergraduate mathematics classrooms. This analysis will provide foundational knowledge about the relationship between active learning instruction and effective learning environments that engage all students. The primary goal of the research is to explore the experience of students and instructors during group activities in these classrooms; closely analyzing their interactions and characterizing learning opportunities (OtLs) within groups. The project team will work with instructors who incorporate teaching practices focused on fostering the engagement of all students in the context of teaching semester-long introductory undergraduate mathematics courses. Specifically, the research will examine the extent to which moving into more central roles of participation is available to all students within small-group social ecologies, carefully attending to the influence of classroom norms and belonging-oriented instruction on these participation shifts. The analysis will center on group interactions and OtLs before, during, and after the participation of instructors in coaching and professional learning opportunities focused on social ecologies and promoting students’ sense of belonging in mathematics. The research will be conducted at two institutions serving different regions of the United States, both of which have had a sustained commitment to active learning in introductory mathematics. The use of two sites will enable the exploration of how OtLs may vary among students in different institutional contexts with established instructional practices. The project will aim to capture comprehensive rich data on students' and instructors’ perceptions of group interactions through surveys, interviews, and classroom observations centered on small groups. The project will seek to provide four major contributions to STEM education research. First, is to advance foundational knowledge about the relationship between active learning instructional approaches and effective learning environments that engage all students. Second, is to broaden explanatory knowledge about students’ OTLs and experiences of belonging in active learning undergraduate mathematics classrooms. Third, is to increase understanding of how students experience sociohistorical and socio-mathematical classroom norms, and how those experiences are associated with OtLs. Fourth, and finally, is to extend core understanding of instructional practices that support effective learning environments in undergraduate mathematics classes. This project is supported by NSF's EDU Core Research (ECR) program. The ECR program emphasizes fundamental STEM education research that generates foundational knowledge in the field. Investments are made in critical areas that are essential, broad and enduring: STEM learning and STEM learning environments, broadening participation in STEM, and STEM workforce development. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

Opioid use disorder (OUD) is a leading cause of death, with disparities in morbidity and mortality widening by race, ethnicity, sex and gender. Medications for OUD are life-saving; increasing their access, utilization and retention is the most effective pathway forward to combat this public health crisis. Comorbid conditions com- mon among people with OUD, such as insomnia, hinder OUD treatment benefit, rendering patients at persis- tent overdose risk. Insomnia is prevalent in the majority of patients receiving buprenorphine for OUD, regard- less of a patient’s stage in recovery, representing an ideal target for adjunctive relapse prevention treatments. Using the innovative NIDA Phenotyping Battery (PhAB), our group has identified a multidimensional profile, or ‘phenotype’, among individuals with OUD and SUD that encompasses both sleep and co-occurring neurofunc- tional domains (i.e., reward, negative emotionality, metacognition). We hypothesize that symptoms related to this constellation of neurofunctional domains in OUD are associated with the brain’s orexin system, which reg- ulates homeostasis, playing roles in sleep, reward and the stress response. This hypothesis is consistent with preclinical studies highlighting how targeting the orexin system reduces opioid self-administration in animal models. Identifying the full constellation of neurofunctional mechanisms underlying how the orexin system im- pacts OUD could illuminate multiple targets to advance treatments and medication development. We propose a mechanistic study to investigate how targeting the orexin system affects symptoms related to the neurofunc- tional domains identified in our prior phenotyping work through a clinical trial of participants with OUD on bu- prenorphine. Deep phenotyping, such as with the NIDA PhAB, has been touted as a method to achieve preci- sion medicine in addictions via tailoring treatments to individuals’ biopsychosocial profiles. This comprehensive approach, especially when coupled with health equity assessments, is warranted for this investigation at the intersection of sleep and addictions given the interplay between socioecological contexts and individual-level factors that shapes these conditions’ trajectories. We will utilize lemborexant, an FDA-approved dual orexin receptor antagonist, building upon our group’s phase 1 study indicating its safety and tolerability among outpa- tients with OUD receiving buprenorphine. We will examine the detailed effects of pharmacologically antagoniz- ing the orexin system with lemborexant on the NIDA PhAB pre-specified four neurofunctional domains we hy- pothesize are underlying OUD treatment benefit over a 2-month follow-up: sleep (Aim 1), reward, negative emotionality, and metacognition (Aim 2). In line with precision medicine, a health equity lens and the Trans-NIH Strategic plan for Women’s Health Research, we will harness our team’s complementary expertise to also ex- plore associations of intervention responses by sex, behavioral, and select biopsychosocial variables using our established deep phenotyping procedures (Aim 3). Results will advance our understanding of the neurofunc- tional mechanisms engaged by orexin targets underlying OUD treatment response.

NIH Research Projects · FY 2025 · 2024-09

Disease burden, healthcare delivery, health outcomes, and life expectancy differ strikingly across US populations and communities. To set priorities and focus research where needed, translational science teams and communities need to co-create data systems that allow them to identify different health outcomes—positive and negative—and potential underlying causes; track trends, including the impact of their work; and collaborate to develop priorities and solutions. The Wright Regional CCTS is a national leader at developing census tract measures to inform research, training, care, and policy. Our CTSA hub has developed the HealthLandscape Virginia geospatial and analytic data warehouse with novel community-level metrics for every community in Virginia that span workforce, clinical care, community characteristics, social and economic factors, and health outcomes. We have used HealthLandscape and a novel bright spot and community asset mapping analysis, a blend of advanced analytics and community engagement, to identify communities that do better or worse than predicted for opioid overdose deaths and potential causal factors. This approach needs to be expanded to a wider range of health topics. Building on existing data, analytics, strengths in community engagement, and HLVA platform, we propose to develop the Virginia Accountable Health Engagement and Action Dashboard (Va-AHEAD). Our work will occur in four phases: (1) prioritize and co-create with the community new health topics and measures, (2) identify bright spot communities that do better than expected and factors that may contribute to their success, (3) develop shared meaning, products, and action from the data, and (4) disseminate and support use for improving health. To develop content, we will use unique person-level data (All-Payer Claims Database, state mortality data) for every person in Virginia, community-level data sources, and authentic community engagement grounded in community-based participatory research and guided by our bright spot and community asset mapping approach. Content will be configured in Va-AHEAD. For each health topic, one of seven existing community advisory boards will support content development and usability design of content. We will form a new Health Research Opportunity lab, a learning community to support use of the dashboard and products. Milestones to demonstrate success include: (1) engage community partners to prioritize and coproduce content, (2) calculate new health measures, (3) identify bright and cold spot communities and their health solutions and needs, (4) engage researchers, learners, care team members, and policymakers to use the dashboard, and (5) longitudinally track Va-AHEAD use and impact on translational science and health outcomes. These efforts will address a longstanding translational science need—new data and analytics for health outcomes research determined by the communities that need assistance. The lessons and infrastructure emanating from this project will produce a sustainable model that is scalable across the CTSA consortium.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY / ABSTRACT Fear of cancer recurrence (FCR) is alarmingly high among patients with primary malignant brain tumors, who face the certainty of tumor recurrence given the current insufficient curative treatment options and who will experience a resultant lifetime of oncological and neurological sequelae. Moderate-to-severe levels of FCR can have dire consequences for cancer patients, such as impeding daily function, activating maladaptive coping patterns, and reducing medical treatment adherence. FCR also plays a significant role in the lives of family members—our work shows rates of FCR among brain tumor caregivers are higher than the patients themselves. Despite this, existing psychological interventions targeting FCR are not translatable to neuro-oncology and contain discriminatory inclusion criteria prohibiting our brain tumor patients and caregivers from participation. In response to this historic inequity and the vital need, our team developed FearLess: a novel, evidence-informed, mindfulness-based, cognitive-existential, manualized psychological intervention targeting FCR in neuro- oncology populations. However, study feasibility and acceptability issues remain. We identified three information gaps specific to recruitment methodology, study population suitability, and control group feasibility in need of resolution prior to FearLess protocol finalization and intervention implementation in larger-scale trials. First, to identify ideal recruitment methods, we need to evaluate the feasibility of a cohesive multimodal national recruitment strategy for both neuro-oncology patients (n=40) and caregivers (n=40). Second, to refine the appropriate study population, we need to examine the feasibility and acceptability of the FearLess intervention and associated study procedures across stratification groups (recurrent status and participant role). Lastly, to investigate the appropriateness of a control group, we need to assess the feasibility and acceptability of a randomized waitlist-control in both patients and caregivers. As such, the proposed study is a Phase IIb randomized waitlist-controlled trial, per the NIH ORBIT Model, assessing the feasibility and acceptability of recruitment strategies, target population, and appropriateness of a waitlist control group in order to finalize the protocol of FearLess for primary malignant brain tumor patients and caregivers. Eighty participants will be randomized to either immediate intervention or waitlist control. Randomization will be stratified by recurrence status (newly diagnosed or recurrent) and participant role (patient or caregiver). Recruitment strategy will be evaluated by outlet yield and cost. We will assess feasibility and acceptability metrics throughout enrollment, intervention, and follow-up periods including screening completion rate, eligibility rate, enrollment rate, intervention adherence, intervention satisfaction, as well as retention, and evaluate whether these metrics differ between multifactorial stratification groups (newly diagnosed v. recurrent; patients v. caregivers). Given the underrepresentation of neuro-oncology in FCR studies, this study will yield critical knowledge prior to finalizing the FearLess protocol for larger-scale trials.

NIH Research Projects · FY 2025 · 2024-09

SUMMARY Substance use disorder (SUD), including use of the psychostimulant amphetamine (AMPH) and its congeners, is on the rise, especially in the Covid-19 pandemic era. There are no effective medications available for psychostimulant SUD, likely because of the lack of thorough understanding of the complex neurobiology underlying the disease. Noradrenergic neurotransmission in the mesolimbic circuit plays a critical role in SUD. AMPH inhibits norepinephrine (NE) transporter (NET) activity promoting its behavioral effects. NET, a principal mediator of NE signaling, is regulated by post-translational modifications, such as phosphorylation and protein- protein interactions. These regulators of NET are impacted by psychostimulants, including amphetamine, in turn impacting the stimulant and rewarding effects of these drugs. However, to date, post-translational modifications have not been a focus of investigation in the SUD field. Our published studies over several years demonstrate that the The258/Ser259 motif, a phospho-site in the NET, plays a pivotal role in regulating AMPH-evoked behaviors. In this proposal, we explore this novel finding using cutting-edge techniques, including a phosphorylation-defective NET-Thr258Ala/Ser259Ala mutant mouse model (NET-T258A/S259A), a viral- mediated brain region-specific blockade of NET-T258/S259 phosphorylation, and recordings of extracellular NE dynamics in vivo using high-speed chronoamperometry and microdialysis. With these new models and tailored biochemical, neurochemical, and behavioral studies, the current proposal aims to fill critical gaps in our understanding of the central role of NET phosphorylation in AMPH-evoked NE dynamics and animal behavior. As a key mechanism, we have discovered that NET-T258A/S259A mice exhibit genotype- and sex-specific alterations in AMPH sensitivity in addition to brain-region specific variations in NET function and expression. Here, we will expand and test our overarching hypothesis that brain region-specific T258/S259-dependent NET phosphorylation and regulation contributes to sex-specific AMPH-induced behaviors relevant to addiction and reward. Aim 1 will investigate NET regulatory phenomena including NET phosphorylation and NET subcellular distribution and protein-protein interactions in the prefrontal cortex and nucleus accumbens to determine the relationship between T258A/S259A mutant-dependent dysfunction in AMPH-mediated NET regulation and in AMPH-evoked behaviors. Aim 2 will evaluate brain-region specific roles of T258/S259-dependent NET regulation in AMPH reward using adult DBH-Cre mice expressing the NET-T258/S259 motif in a NE-terminal specific manner. Aim 3 will examine the impact of T258/S259-dependent NET phosphorylation and regulation on NE dynamics (release and clearance as well as extracellular levels) modulated by AMPH in vivo. Outcomes from proposed studies will provide novel insights into the mechanisms of SUD, open new avenues for examining T258/S259-phosphorylation dependent NET regulation as an underlying mechanism of AMPH’s actions and provide new molecular therapeutic intervention points.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Oral health is essential for the overall health and well-being of adults, yet oral diseases remain prevalent within this population. It is estimated that 90% of United States (U.S.) adults aged 20 to 64 years have experienced dental caries, and nearly 60% of adults aged 65 years or older have periodontitis. Adults of Central and South American ancestry, in particular, experience notable differences in oral health outcomes, including the highest prevalence of periodontal diseases compared to their counterparts. Research exploring the reasons for their increased risk of oral diseases has often focused on acculturation—broadly understood as the process of adopting to U.S. societal norms, practices, and behaviors. However, such cultural explanations that emphasize individual-level adaptations tend to overlook broader upstream influences that contribute to oral health challenges over the life course and across generations. Therefore, the purpose of the proposed study is to examine how everyday experiences shaped by upstream psychosocial factors influence oral health among adults of Central and South American ancestry. To advance this undertheorized area of research, this project will leverage electronic dental records to examine the association between perceived exposure to psychosocial stress and both clinical and self-reported oral health, while evaluating differences by biological sex, behavioral risk factors, and neighborhood-level economic conditions. The knowledge generated from this study will advance understanding of the mechanisms by which broader upstream contextual factors influence oral health. This study is novel in moving beyond individual-level frameworks to focus on broader systems and conditions that shape access to and outcomes in oral health. Findings will contribute to advancing the goals outlined in NIDCR’s 2021-2026 strategic plan goal to improve scientific methods for understanding and addressing variation in dental, oral, and craniofacial health and disease.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract The chemotherapeutic drug cisplatin is a first-line drug for the treatment of many solid tumors, especially head and neck squamous cell carcinoma (HNSCC). However, resistance to cisplatin has become a major obstacle to effective cancer therapy. Cisplatin is well-known to enrich the cancer stem cell (CSC) population, which can contribute to chemoresistance. Accordingly, targeting CSCs may represent an effective strategy to overcome cisplatin resistance. Previously, we demonstrated that FOSL1 promotes tumorigenesis and metastasis of HNSCC through establishing Super-Enhancers (SEs) at key cancer stemness and pro-metastatic genes, and furthermore, disruption of FOSL1-SEs suppresses HNSCC growth and metastasis. Additionally, we have discovered that increased FOSL1 activity facilitates cisplatin resistance of CSCs in a spontaneous mouse model of HNSCC. Taken together, we believe that the FOSL1-SE-dependent transcription program may represent a novel target for overcoming cisplatin resistance in HNSCC. To validate this, the key scientific questions of whether FOSL1-SEs are present in cisplatin-enriched CSCs and how to determine their functional properties must be addressed, as these FOSL1-SEs were originally characterized using whole HNSCC cell populations only. Currently, no effective FOSL1 inhibitors are available, which hinders our further mechanistic and functional studies. Proteolysis Targeting Chimeras (PROTAC) is a novel approach to selectively and potently degrade a protein of interest (POI) both in vitro and in vivo. In this approach, a hetero-functional molecule is designed to contain an inhibitor that binds to a POI, another small-molecule ligand which binds to an E3 ubiquitin ligase complex, and a linker to tether these two ligands together. In our preliminary studies, we have designed and synthesized a group of novel PROTAC-based FOSL1 degraders, from a parental FOSL1 inhibitor. The top compound can potently degrade FOSL1 to eliminate CSCs in vivo, displaying advantages over the parent inhibitor. Therefore, we hypothesize that FOSL1-SEs determine the functional properties of cisplatin-enriched CSCs in HNSCC, and serve as a promising target for overcoming cisplatin resistance in HNSCC, which can be validated by utilizing the effective PROTAC-based FOSL1 degraders. We propose the following specific aims to test our hypotheses. Aim 1: Investigate the mechanism of action of FOSL1-SEs in determining the functional properties of cisplatin-enriched CSCs in HNSCC and apply PROTACs to validate such a mechanism of action. Aim 2: Initiate SAR studies and a functional screening to identify the top PROTACs to target FOSL1-SEs effectively in HNSCC from a library of 100 candidates. The goal is to identify optimal compounds for mechanistic (Aim 1) and functional validations (Aim 3). Aim 3: Validate whether targeting FOSL1-SEs with PROTAC molecules (top 2 compounds from Aim 2) can efficiently eliminate CSCs and overcome cisplatin resistance using mouse models of HNSCC. The successful completion of this study will provide a novel and validated drug target and contribute to the development of new strategies for improving HNSCC chemotherapy outcome.

NIH Research Projects · FY 2024 · 2024-09

PROJECT ABSTRACT/SUMMARY Background: Institutional change in higher education regarding diversity, equity and inclusion, tends to be complex, contested, and slow moving. However, many institutions continue to design and implement change programs. Among those are gender equity initiatives that aim to increase the participation and advancement of diverse women faculty in the science, technology, engineering, mathematics, and medicine (STEMM) academic and research workforce. Despite these efforts and initiatives, many institutions continue to face structural barriers to the change programs they attempt to implement. What is missing is a central hub to support and advance gender equity programs through collecting, validating, evaluating and disseminating strategies and outcomes. Such a resource would provide the necessary tools, strategies, and techniques to optimize gender equity programs collaboratively across STEMM disciplines. Aims: The proposed National Coordinating Center for Advancing Gender Inclusive Excellence (AGIE) at Virginia Commonwealth University (VCU) intends to fill this gap. In collaboration with the National Institutes of Health (NIH), the VCU AGIE will create an online central repository for sharing resources, tools, technologies, expertise, and strategies designed to overcome systemic gender-based inequities impacting the STEMM academic and research workforce. Stakeholders will be able to search for strategies to identify and address systemic gender-based inequities and enable women to attain leadership positions in STEMM research. The aims of the VCU AGIE are to: 1) Evaluate the types and components of programs that substantially increase the participation and advancement of diverse women faculty in the STEMM academic and research workforce; 2) Develop a central repository for data, tools, programs, and strategies that promote gender equity at the faculty and leadership levels in the STEMM academic and research workforce; and, 3) Promote and disseminate research on barriers and strategies to enhance the recruitment, retention and advancement of STEMM women faculty and leaders in the academic and research workforce. Impact: The primary outcome of accomplishing these aims will allow the VCU AGIE, in collaboration with the NIH, to set a national standard of excellence for advancing diverse women in faculty and leadership positions across the STEMM fields. By accomplishing this goal, this program will create a functional, validated, and sustainable resource to overcome systemic gender-based inequities impacting the STEMM academic and research workforce.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Lifetime Alcohol Use Disorder (AUD) has an estimated US lifetime prevalence of 29.1%. Major Depressive Disorder (MDD) is often comorbid with AUD, with an estimated lifetime AUD prevalence of 40.8% among those with lifetime MDD. This comorbidity was unequally distributed by sex globally, with prevalence nearly twice as high in men as in women. AUD and MDD are moderately heritable, with and a substantial proportion of the underlying genetic liability between AUD and MDD is shared, (rg = 0.56). The temporal order of the disorders is complex and likely differs by sex. This project proposes to leverage data from 10 existing collections from longitudinal, diverse ancestry cohorts to analyze the interacting sex, genetic, and co-morbid MDD effects on the trajectory of AUD. These analyses represent modeling approaches not previously applied in these datasets and successful completion of the proposed research will elucidate biological mechanisms of alcohol etiology by investigating sex-specific and time-varying genetic influences on item-level measures of AUD. Importantly, this proposal also includes development of novel machine learning (ML) approaches for predicting missing and/or unmeasured AUD outcomes from existing, biobank-scale data to improve power for genetic analyses. This K award will provide the structured training and mentorship in molecular genetics for complex traits and ancestrally diverse samples as well as psychiatric nosology and epidemiology necessary for the candidate to develop the expertise needed to support her goal of becoming an independent and innovative researcher in alcohol epidemiology. Combined with her background in biostatistics and analytical methods, the proposed training and research activities will develop her capacity posit the kinds of research hypothesis, comprehensive plans, and wholistic, innovative approaches which are most relevant to advancing science and medicine in alcohol research. In sum, with dedicated mentoring, the planned training and research will equip the candidate to establish a strong line of competitive research supporting a long-term goal of an independent research plan that integrates novel statistical and computational approaches to elucidate the genetic and environmental factors and interactions contributing to AUD.

NIH Research Projects · FY 2025 · 2024-09

Psychological distress is an important component of cancer care, and can adversely affect treatment compliance, quality of life and survival. Data about psychological distress in breast cancer survivors is sparse. This is an important gap given the adverse impact of psychological distress on breast cancer outcomes. The purpose of the proposed research, “An In-depth Examination of Psychological Distress in Breast Cancer Survivors,” is to gain a detailed understanding of the unique role of multilevel factors on the psychological distress experience of breast cancer survivors, and how survivors cope with breast cancer related psychological distress. This is essential to identify potentially modifiable factors for distress management interventions in breast cancer survivors. A highly qualified multi-disciplinary team has been assembled to support my research and training goals. The predoctoral (F99) research project is a mixed methods study guided by the model of cancer related worries, study aims are to: 1a) examine levels of psychological distress over time by age, and associations between sociodemographic factors, clinical factors, and psychological distress, using an existing longitudinal cohort study controlling for clinical factors; 1b) evaluate the contribution of healthcare delivery and psychosocial factors on psychological distress among breast cancer survivors, using an existing longitudinal cohort study; 1c) determine if healthcare delivery and psychosocial factors mediate and/or moderate the association between non-modifiable factors (age) and psychological distress; 1d) determine if healthcare delivery and psychosocial factors mediate and/or moderate the association between non-modifiable factors (age) and psychological distress. The postdoctoral (K00) research project’s goal is to understand breast cancer survivors’ strategies to cope with psychological distress. Utilizing Strauss and Corbin’s grounded theory methodology and a community engaged approach, study aim is to 2) understand young breast cancer survivors’ strategies for coping with psychological distress, using in-depth interviews. The proposed research aligns with NCI’s key research area of cancer survivorship, which among other issues prioritizes addressing psychological concerns in cancer survivors.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Youth in foster care have unique experiences and significantly higher trauma load which greatly increase their risk for a range of negative social, behavioral, academic, physical and mental health outcomes. However, despite documentation of many negative outcomes associated with child welfare involvement, there remains heterogeneity in outcomes from foster placement. Most research concludes that foster care is not a cause of worsened outcomes, and that supportive and stable foster care environments have the potential to improve child wellbeing in the short and long term. Given this, more research is warranted to understand the risk and protective factors present for foster youth which may be modified through the foster care environment and caregiving. Understanding what differs from child and caregiver perspective, between those who experience better and worse outcomes, is critical for understanding how to increase likelihood of positive development following foster care placement. The overarching goals of this K08 proposal are threefold. First, the study aims to use existing large-scale longitudinal data collected on youth in the child welfare system to explore critical risk and resilience factors for youth in foster care and whether these are moderated by transracial placement. Second, this study aims to document the parenting practices used by foster parents, their thoughts on the trainings they receive, and their perception of the impact this has on their foster child's functioning. Third, this study will interview key stakeholders (e.g. child welfare workers and foster parents) to assess the current barriers and facilitators of current foster parent trainings, as well as their perception of topics covered and gaps in training, in order to inform future intervention adaptation or development. To achieve these aims, the candidate and multidisciplinary mentorship team have developed a comprehensive training plan that delineates a series of training and research goals. These goals will incorporate training in quantitative and qualitative research methods, as well as intervention development and evaluation. The training and resultant findings will capitalize on existing expertise and provide additional, focused training to allow for the development of a multimodal research program that will position the PI to lead future federally funded multidisciplinary studies with translational implications for populations of youth who experience trauma and/or parental separation. The proposed research represents an important contribution towards advancing our understanding of the risk and protective factors present for youth in foster care, and how to support foster parents through parenting intervention in order to improve adjustment outcomes for foster youth. The institutional environment is ideal for the candidate's goal of developing an independent research line that ultimately aims to improve the psychosocial outcomes for youth who experience parental separation.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Idiopathic Pulmonary Fibrosis (IPF) is a progressive scarring disease with limited therapeutic options. Fibrotic lung diseases are characterized by an accumulation of excess extracellular matrix (ECM), contributing to the destruction of lung architecture, inability to perform gas exchange, and even death. My mentor published pioneering work that IPF patients have abnormally high levels of lactate in their lungs. Lactate in turn decreases the local pH, which activates latent TGFβ, resulting in a pro-fibrotic feed-forward loop that drives fibrosis and dysregulated metabolism. We and others have demonstrated that increased tissue stiffness in lung fibrosis also drives fibroblast differentiation, expression of matrix proteins, and cross-linking, resulting in further increases in tissue stiffness. While tissue stiffness and altered lactate metabolism are independently recognized as pathogenic pathways and potential therapeutic targets, I have now identified the mechanoreceptor Piezo2 as a potential link between altered tissue mechanics and aberrant metabolism. In this revised project application, I will use patient-derived non-fibrotic and IPF lung fibroblasts to characterize the mechanism by which Piezo2 drives metabolic adaptations in response to increased matrix stiffness, and how these metabolic adaptations contribute to a feed-forward loop that drives fibrosis. I will also use well-characterized pre-clinical mouse models of pulmonary fibrosis to investigate the role of Piezo2 in vivo using genetic knockdown and pharmaceutical inhibition approaches. To further support the clinical relevance of my results, the metabolic adaptations identified in the cell culture and mouse models will be compared with my new evidence of metabolic disruptions in the lungs of IPF patients obtained by metabolomics analysis of exhaled breath condensate. This project will support my career goal to transition to a tenure-track faculty position as an independent investigator. To complete my technical training needs for this project, I will work with my co-mentor Dr. L. Ashley Cowart to participate in extensive hands-on training in metabolomics data analysis, as well as attend training courses at the highly regarded West Coast Metabolomics Center at UC Davis. My co-mentor Dr. Patricia Sime will guide me in my professional development as an independent scientist by providing additional training opportunities in translational research, grant writing and scientific communication, lab management and administration, teaching, and mentoring others. I have established a strong mentor committee and strong relationships with internal and external collaborators. Virginia Commonwealth University is a highly productive scientific environment and is very supportive of my development as an independent scientist. My training and research experience under this career development award will yield novel insights into the pathogenic mechanisms of pulmonary fibrosis, giving me foundational skills and my own research project to carry me into independence.

NSF Awards · FY 2024 · 2024-09

Non-technical Description: Gallium nitride (GaN) and related III-nitride alloys (AlGaN) form the basis for modern optoelectronics, including bright blue and white light-emitting diodes (LEDs) and lasers. Bright deep ultraviolet (DUV) LEDs with wavelengths less than 300 nm are the only alternative technology to replace bulky mercury lamps in numerous applications, including gas sensing, phototherapy, air and drinking water purification, large-scale disinfection, and sterilization of public areas. The main obstacle to this semiconductor technology is the need for conductive p-type AlGaN - a semiconductor material with added dopant impurities that greatly improve its properties. Currently, Mg is the only available p-type dopant for these devices. Unfortunately, the efficiency of these LEDs for wavelengths below 270 nm rarely exceeds 1%. The principal investigators and their research team use beryllium (Be) as an alternative p-type dopant for GaN and AlGaN. Their preliminary results show that Be impurity or Be-containing complexes are very promising for the realization of conductive p-type III-nitride materials that could be used in future bright DUV LEDs. The proposed research program impacts the education of under-represented minorities at VCU, which in 2022 has been designated a Minority Serving Institution by the US Department of Education. Collaboration between SUNY-Albany and VCU forms a strong foundation for research and education in both institutions. This project also strengthens international collaboration with researchers at the High Pressure Institute in Poland – the world leaders in the growth of bulk GaN and studies involving ultra-high pressure. Technical Description: This project uses an innovative idea to create Be-related complexes, such as Be-O-Be, to achieve high-conductivity p-type AlGaN semiconductor alloy. The research team’s preliminary experimental and theoretical results indicate that highly efficient p-type III-nitride materials are feasible. Fabrication of conductive p-type AlGaN produced by in-situ Be-O co-doping or ion implantation is a novel approach to significantly improve device performance for solid-state lighting, especially the bright DUV LEDs. SUNY’s team is the only research group in the world to grow Be-doped GaN and AlGaN using the metalorganic chemical vapor deposition (MOCVD) technique, which has proven to be the most efficient method for developing bright white and UV LEDs. First-principles calculations and detailed characterization studies, including temperature-dependent Hall effect, photo- and cathodoluminescence, provide valuable feedback to the growth/implantation efforts. The ultimate goal is to achieve reliable p-type AlGaN and to gain in-depth understanding of the properties of impurities and defects in III-nitride semiconductors. Understanding co-doping mechanisms may lead to breakthroughs in doping other semiconductors. The research also attempts to explain the properties and identity of point defects unintentionally introduced in GaN, AlN, and AlGaN. This project can potentially develop high p-type conductivity ultra-wide-bandgap III-nitrides and bridge the gap between theorists and experimentalists in this field. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-09

This project will study how changes in population numbers and the process of adaptation contribute the to formation of new species in pines. Species represent the basic units by which biodiversity is quantified. It is thus paramount to understand the processes affecting the formation of new species, especially as accelerated environmental change threatens numerous species with extinction. A key component to the formation of new species is the development of reproductive isolation, defined as the reduction and eventual cessation of genetic mixing among populations. Despite more than a century of research into the the ecological, genetic, and developmental drivers of speciation across diverse organisms, there remains gaps in our understanding of the processes that lead to the formation of reproductive isolation. This project attempts to fill these gaps for pines, a group of ecologically dominant and economically important temperate plants displaying enormously variable levels of reproductive isolation. Filling these gaps is crucial to ensure the long-term survival of pines as changes to their habitats continue to accelerate. As such, the next generation of forest scientists must be diverse, multidisciplinary, and well trained. This project will train the next generation of diverse forest scientists in cutting edge methodologies, develop teaching modules about pine and tree diversity for local elementary schools, and expand existing resources and training for forest managers to better understand the role of hybridization (i.e., the lack of reproductive isolation) during evolutionary responses to changing environments. The relative roles of demography and adaptation to standing levels of reproductive isolation for pines will be quantified using a two-tiered combination of phylogenetics, genomics, demographic inference, and landscape genomics. First, phylogenetically informed meta-analyses will relate interspecific crossing rates to climate niche similarities (adaptation surrogate) and range size (demography surrogate) across the entire genus. Existing data suggest that each predictor significantly affects reproductive isolation for pines. Second, exon-based, pull-down sequencing of tens of thousands of genic regions in a reduced set of species will be used to test the hypothesis that climate adaptation and accumulation of deleterious genetic load within species as a function of demographic history are the primary determinants of crossing rate variability for pines. These efforts capitalize on the unique biology of pines (e.g., large genome size, rapid decay of linkage disequilibrium, polyembryony) relative to other well-studied plant systems and will provide foundational information for further comparative studies across long-lived plants. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-09

Summary Few safe and effective pharmacotherapies exist for alcohol misuse. Alcohol consumption directly effects the gut microbiome, altering its diversity and leading to increased bacterial overgrowth. Chronic drinking leads to microbial dysbiosis, intestinal permeability (“leaky gut”) and changes in immune responses. These microbiome changes have been associated with other neuropsychiatric symptoms such as anxiety and depression, frequently associated alcohol misuse symptomology. A growing number of clinical and pre-clinical studies have provided remarkable promise using fecal microbiota transplant (FMT) as a safe, effective therapy for reducing ethanol drinking and liver disease. Our own collaborative efforts have recently shown that FMT improved drinking behavior in humans with cirrhosis, and this was transmissible to germ-free mice through alterations in the gut immune-inflammatory response. Since fecal transplant of microbiota from patients with AUD can change the intestinal barrier and affect brain function, we hypothesize that gut microbiota enriched in beneficial bacteria can reduce ethanol drinking and related anxiety-like behaviors. Dietary fiber may further enhance this effect by increasing microbial engraftment or length of its effect. This innovative mPI proposal brings together the specific expertise of human clinical laboratories experienced in using therapeutic FMT and a rodent behavioral pharmacology laboratory to understand the specific characteristics of gut microbiota needed to reduce ethanol intake and preference. In Aim 1, we will assess the effects of microbiota transplant into recipient mice from human donor with varying amounts of Lachnospiraceae and Ruminococcaceae on ethanol drinking, FMT engraftment and anxiety-like behavior. Four human donor samples will be assessed which differ in the amount Lachnospiraceae and Ruminococcaceae. In Aim 2, we will evaluate the role of dietary fiber on microbiome engraftment and its ability to further reduce ethanol drinking in mice. These innovative studies are an important first step in understanding the mechanisms through which gut microbiota can positively affect the gut-brain-axis to reduce ethanol drinking and related phenotypes. These studies will establish a pre-clinical model of therapeutic FMT where we can begin to test the specific mechanisms of these drinking reductions.

NIH Research Projects · FY 2025 · 2024-09

Primary sclerosing cholangitis (PSC) is a major cholestatic liver disease with high morbidity and mortality. Inflammation and fibrotic injury of the bile ducts due to impairment of bile formation or flow represent the major characteristics of PSC. A large fraction ( about 98%) of the transcribed mammalian genome is noncoding RNAs (ncRNAs), including long noncoding RNAs (lncRNAs), circular RNA (circRNAs), and microRNA (miRNAs). However, the biological functions of ncRNAs remain largely unknown. As the first identified and well- characterized lncRNA, aberrant expression of lncRNA H19 has been associated with numerous human diseases, including liver diseases. CircRNAs are a large emerging class of ncRNAs that are important regulators of various physiological and pathological processes. Recent advances in high-throughput RNA sequencing and circRNA- specific bioinformatics algorithms have identified thousands of circRNAs with tissue-specific expression patterns. However, the relevance and function of circRNAs in disease, especially in liver diseases, remain to be determined and is the focus of this new application. We reported that aberrant expression of H19 is associated with the severity of cholestatic liver injury in Mdr2-/- mice. Our new preliminary data showed that 1) Key genes involved in inflammation, fibrosis, and senescence, as well as sphingolipid metabolism, were upregulated in both bile duct ligation (BDL)-mice and Mdr2-/- mice; 2) The number of cholangiocytes, pro-inflammatory macrophages and activated stellate cells were significantly increased, while the number of Kupffer cells (KCs) was significantly reduced in Mdr2-/- mice; 3) Deletion of H19 reduced cholestatic liver injury in both BDL and Mdr2-/- mice; 4) The deletion of RNA binding protein HuR (human antigen R) upregulated H1926. 5) Arraystar circRNAseq identified 33 overlapping circRNAs, which were significantly upregulated in Mdr2-/- mice and downregulated in Mdr2-/-/H19- /- mice. Among them, mmu_circRNA_26644 (circRNA-Edil3) and mmu_circRNA_19966 (circAff3) are among the most significantly regulated circRNAs by H19; 7) Sequence analysis suggested that circRNA-Edil3 and circAff3 may serve as a "sponge" for miRNA-215-3p, miRNA-129-5p, miRNA-212-5p, and miRNA-185-3p; 5) Previous studies have shown that these miRNAs inhibit HSC activation and suppress fibrogenic signaling pathways by targeting high mobility group box protein 1 (HMGB1), Edil3 and Aff3. Based on our published results and a large amount of exciting new preliminary data, we HYPOTHESIZE that H19-induced upregulation of circRNAs plays a critical role in cholestatic liver fibrosis by sequestering miRNAs and HuR. Two specific aims are proposed to test our hypothesis. Aim 1 is to examine the role of H19-induced upregulation of circRNAs (circEdil3 & circAff3) in regulating cholangiocyte proliferation, senescence and hepatic inflammation. Aim 2 is to identify the mechanisms by which H19-induced circRNAs promote cholestatic liver injury. Completion of our proposed studies will elucidate the potential cellular/molecular mechanisms involved in the progression of cholestatic liver diseases and identify novel diagnostic and therapeutic targets.

NIH Research Projects · FY 2024 · 2024-09

TITLE: Assessing the Impact of Health System Ownership on Fulfilling the Vision of High-Quality Primary Care and Whole Health PROJECT SUMMARY The National Academies of Sciences, Engineering, and Medicine’s (NASEM) reports “Implementing High Quality Primary Care'' and “Achieving Whole Health: A New Approach for Veterans and the Nation'' call for coordinated systems level approaches to care.1,2 In response to these calls for action and stresses on primary care from the COVID pandemic and other market forces, primary care practices are increasingly owned by health systems. In Virginia we have documented that between 2018 and 2022 there was an increase from 25% to 43% of practices being owned by a health system with a concurrent decline in clinician ownership.3 These changes could both help (e.g., provide a systems level approach, expanded interprofessional teams, new resources) and/or undermine (e.g., reduce local decision-making authority, replace ambulatory focus with hospital interests, undermine organizational culture) the ability to achieve NASEM’s vision. We propose an explanatory sequential mixed-methods study using multimedia elicitation surveys and focus group interviews to assess the impact of ownership on high-quality primary care and whole health care and to describe contextual factors that may impact care. Building on our ongoing, longitudinal assessment of primary care in Virginia conducted in the Ambulatory Care Outcomes Research Network (ACORN), we will randomly sample 30 primary care practices throughout the state, stratified by practices that in the past 5 years (a) moved from clinician to hospital ownership, (b) stayed clinician owned, or (c) stayed hospital owned. The survey will consist of a brief multimedia presentation, developed in collaboration with the NASEM report authors, of the key elements of high-quality primary care and whole health, immediately followed by Likert scale questions to assess team members’ attitudes, current practice, and confidence in the ability to improve on these elements. The survey will be digitally administered with REDCap software to representatives of each clinical team member type. To develop the multimedia elicitation survey, we will work with the NASEM report authors and committee members to distill and operationalize core elements articulated in the reports, including questions on equity, accessibility, integration, interprofessional teamwork, professional satisfaction and team wellbeing, and community engagement. A practice structural questionnaire will also collect information on practice organization and staffing levels, patient volume and population demographics, payer mix, EHR capabilities, enhanced access options, and participation in innovative payment models. Follow-up group interviews with practice teams will reflect on team survey responses and assess the organizational, practice, and individual level factors influencing high-quality primary care and whole health care. Study findings will be used to further AHRQ’s mission of revitalizing the Nation’s primary care system, promote the NASEM vision of Whole Health in primary care, and develop future interventions to help primary care deliver high-quality and whole health care in diverse ownership settings.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY 1 Cancer survivors that use tobacco are at a greater risk of experiencing negative health outcomes. While many 2 cancer survivors quit using tobacco at time of diagnosis, available research demonstrates that many 3 relapse (e.g., 13-60%). The Social Ecological Model (SEM) provides a conceptual framework for 4 understanding the intrapersonal factors and interpersonal factors that may contribute to tobacco use relapse. 5 However, to date, few studies have identified intrapersonal and interpersonal predictors of tobacco use relapse 6 among this patient population. Further, these studies utilize survey designs that are unable to examine the 7 factors that immediately precede tobacco relapse. Thus, it is relatively unknown how intrapersonal and 8 interpersonal factors relate to tobacco relapse within the context of cancer survivorship in real-time. 9 The proposed study aims to address this critical gap and advance cancer prevention and control science 10 through using multiple survey methods (i.e., ecological momentary assessment, longitudinal survey) to 11 examine the momentary and long-term associations between intrapersonal factors (i.e., cancer worry, negative 12 affect), interpersonal factors (i.e., social support, social constraint), and tobacco relapse behavior. Cancer 13 survivors that demonstrate greater risk of relapse (e.g., newly diagnosed, recently quit using tobacco) (N=122) 14 will be recruited from VCU Massey Cancer Center and asked to complete a baseline survey and a 3-month 15 follow-up survey to examine intrapersonal and interpersonal predictors of tobacco use relapse (i.e., continued 16 tobacco use for > 7 days). A subset of 40 participants will also complete a 14-day ecological momentary 17 assessment (EMA) to investigate momentary intrapersonal and interpersonal predictors of greater tobacco 18 relapse risk (defined as higher urge to use tobacco and lower motivation to abstain from tobacco). Specifically, 19 the applicant aims to: (1) examine daily associations between intrapersonal factors (i.e., cancer worry, negative 20 affect) and tobacco relapse risk across a 14-day period; (2) examine daily associations between interpersonal 21 factors (i.e., social support, social constraint) and tobacco relapse risk across a 14-day period; and (3) examine 22 the association between baseline intrapersonal and interpersonal factors and tobacco use relapse at follow-up. 23 The proposed training goals for this NRSA fellowship are: (1) increase the applicant’s knowledge of the factors 24 that contribute to tobacco use and tobacco relapse among cancer survivors; (2) enhance training in advanced 25 quantitative statistical methods; and (3) improve translational research-related skills. This training plan involves 26 a variety of research, didactic and professional development-related activities that will facilitate the successful 27 completion of the proposed project and equip the applicant with the skillset needed to lead a career as an 28 independent researcher. Further, the applicant’s mentorship team includes experts within the field of cancer 29 prevention and tobacco control who maintain a history of collaboration. Overall, results from this project have 30 the potential to inform the development of future tobacco treatment programs for cancer survivors.

NIH Research Projects · FY 2025 · 2024-08

Project Summary/Abstract Early environmental and genetic influences exert significant effects on risk for Substance Use Disorders (SUDs). Understanding precursors to SUDs, such as externalizing behavior, that come online prior to the initiation of substances allows for earlier identification and potentially, ability to intervene on those phenotypes before behaviors become disorders. This R34 application proposes to establish a bidirectional translational team and generate preliminary data for an R01 application designed to identify both behavioral and genetic risk factors for neurocognitive phenotypes that precede SUDs. Aim 1 will determine the extent to which early life environment influences neurocognitive development and the relationship between neurocognitive development and adult delay-discounting behavior. Aim 2 will identify genomic network signatures of early life resource scarcity from publicly available datasets and determine the extent to which expression of identified hub genes is associated with neurocognitive behavioral outcomes related to substance use disorder. Aim 3 will allow for generation of polygenic risk scores for externalizing-related phenotypes in GWAS datasets and assess the extent to which these polygenic risk scores predict precursors to SUD behaviors such as impulsivity in the ABCD Study. This aim will also determine whether these aggregate genetic risk scores are moderated by aspects of environment within the ABCD Study. Ultimately, the cross-species approach used here will provide support for an innovative R01 that will leverage preliminary data generated by this study to assess the most influential early life moderators of risk behavior development (identified in Aim 3) which can be systematically assessed in a preclinical developmental behavioral framework (established in Aim 1) and mechanistically assessed through cutting-edge neuroscience techniques focused on critical gene targets (identified in Aim 2). This project is strengthened by the translational team with expertise in early life environmental factors impacting neurocognitive development (Dr. Neigh), polygenic risk for externalizing phenotypes and substance use phenotypes in humans, structural and longitudinal modeling (Dr. Bountress), neuroepigenetics of stress and addiction (Dr. Hamilton), and translational rat models of drug addiction and neurocognitive behaviors (Dr. Banks). The research described herein pairs sophisticated modeling via latent profile analyses (LPA) with animal data, proposes to aggregate existing RNAseq datasets to identify candidate hub genes, and integrates approaches that encompass early life resource manipulations, linking these conditions with measures of impulsivity using delay discounting in adulthood.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY The bacterium Treponema denticola (Td) is an important and yet understudied oral pathobiont that is highly associated with periodontitis, necrotic root canals, and endodontic infections. Growing evidence also shows that Td is implicated in several systemic illnesses such as Alzheimer’s disease and oral squamous cell carcinoma. As a keystone pathogen, Td shows various pathogenic traits, e.g., cell adherence and invasion, stimulation of proinflammation, modulation of host immune responses, and inducing osteoclastogenesis (OCG) and alveolar bone loss. However, bacterial virulence determinants associated with these pathogenic traits remain largely unknown. For instance, there is a longstanding conundrum as to whether or not Td produces lipopolysaccharides (LPS), an endotoxin that is of paramount importance to most Gram-negative bacterial pathogens. Early studies indicate that Td produces LPS; however, later reports from different groups uncover that Td produces lipooligosaccharide (LOS), lipoteichoic acids or membrane associated lipids. These inconsistent reports have been a longstanding obstacle to understanding the role of Td in the pathogenesis of periodontitis and other diseases. During the past five years, we have been striving to address this longstanding conundrum by using a multidisciplinary approach combining bioinformatics, genetics, glycomics, immunology, and structural biology along with several cutting-edge techniques and have made significant progress to understanding the chemical structure, biosynthesis, regulation, and pathogenic role of LPS-like fractions purified from Td. Based on these preliminary studies, we hypothesize that, instead of LPS/LOS, Td produces a new class of sulfated glycolipids (SGLs) with a distinct chemical composition and structure, its biosynthesis is regulated in response to biofilm formation, and that this new type of glycolipids plays a critical role in the pathophysiology of Td. To test this hypothesis, the following three aims are proposed: (1) Delineating the chemical composition, glycosidic linkage, and key genetic determinants required for the biosynthesis of SGLs; (2) Elucidating the regulatory mechanism of SGLs and their role in Td cell structure, motility, and biofilm formation; and (3) Investigating the role of SGLs in Td-induced OCS and alveolar bone loss. To the best of our knowledge, this is the first project to mechanistically investigate the chemical composition, glycosidic linkages, biosynthesis, regulation, and roles of SGLs in the pathophysiology of Td. Completion of this project will provide new insights into understanding the glycome of Td and its role in the pathogenesis of oral infections and systemic diseases. In addition, this application will open new avenues to investigate SGLs in other oral pathogens.

NIH Research Projects · FY 2025 · 2024-08

Despite therapeutic advances, the 5-year survival rate from metastatic triple negative breast cancer (TNBC) has not improved significantly for 30 years. As such, significant benefits to patients with advanced breast cancer will result by developing novel therapies, which target advanced metastatic breast cancer. To address this need we screened metastatic cancers for genes which could contribute to metastasis. From this screen we identified MDA-9/Syntenin-1/Sydecan Binding Protein (MDA-9) as a regulator of cancer cell metastasis. Published and preliminary studies using several mouse models of metastasis confirm that inhibiting MDA-9 prevents metastasis and sensitizes progressive metastatic tumors to chemotherapies leading to improved survival. These results support the hypothesis: that targeting MDA-9 with inhibitors will lead to a combinatorial therapeutic approach that simultaneously inhibits both the dissemination and growth/survival of progressive TNBC. We developed an effective small molecule inhibitor of MDA-9 called PDZ1i. Administering PDZ1i in several mouse models of metastatic cancers effectively prevents metastasis and sensitizes metastatic tumors to chemotherapies, supporting our hypothesis. In this application. we propose experiments to better understand how PDZ1i exerts anti-tumor/metastatic effects and if this information can be used to make PDZ1i a better chemotherapy. In Specific Aim 1, we seek to formulate PDZ1i for clinical applications, building upon our preliminary work with a novel nanocrystal technology (PDZ1i-Nano), and to characterize non-cell-autonomous mechanisms by which PDZ1i suppresses tumor growth. Focus will be on the immune system, particularly the infiltration of effector immune cells in response to PDZ1i-Nano treated tumor cells. Experiments will employ TNBC metastatic mouse models, and human patient-derived (PDX) tumors and humanized mice. The precise impact of this recruitment on tumor growth control will be evaluated in this aim. In Specific Aim 2, genome wide datasets will be used to define the signaling pathways, regulatory transcription factors and down-stream gene targets regulated by MDA- 9 to promote cell motility in vitro and metastasis in vivo. In Specific Aim 3, PDZ1i-Nano will be combined with a standard of care (SOC) chemotherapy, paclitaxel (Taxol), to improve the therapy of mouse models of TNBC. These studies will include using PDZ1i-Nano in both an adjuvant and neoadjuvant setting as a means of preventing the appearance of metastases. Experiments will study how PDZ1i-Nano sensitizes TNBC cells or the host cells to the effects of chemotherapies to improve tumor growth control, which are required for PDZ1i to progress into clinical trials. Because the PDZ1i small molecule inhibitor has initial favorable drug characteristics (ADME, pharmacokinetics and toxicity testing), performs well in mouse tumor models, can be combined with FDA approved SOC chemotherapies, the results of this research program could lead to entry into phase I clinical trials, reducing the lag time until benefits could be realized by breast cancer patients.

NIH Research Projects · FY 2025 · 2024-08

OVERALL: SUMMARY Hepatocellular carcinoma (HCC), the primary malignancy of hepatocytes, is a diagnosis with bleak outcomes. With the alarming rise in global obesity incidence, obesity-induced non-alcoholic steatohepatitis (NASH) is becoming a leading cause of HCC. HCC is usually diagnosed at an advanced stage when the tumor is unresectable. The most effective FDA-approved treatment for advanced non-resectable HCC is a combination of anti-PD-L1 (atezolizumab) and anti-VEGF (bevacizumab) antibodies, providing an overall response rate of 27%. Apart from immunotherapy, systemic therapy with tyrosine kinase inhibitors (TKIs, such as sorafenib or lenvatinib) provides only a modest (~3 months) increase in overall survival and causes drug resistance within six months. Recent studies document that immunotherapy may be less effective in patients with NASH-HCC than in HCC patients with viral hepatitis. Thus, there is an unmet need to develop novel and effective modalities of treatment for advanced HCC. This P01 proposal ExpLoiting theErapeutic VulnerAbilities in hepaTocEllular carcinoma (ELEVATE), which involves four projects, an administrative core (Core 1), a mouse model and pathological analysis core (Core 2), and a biostatistics and bioinformatics core (Core 3; BBC), aims to interrogate molecular changes in HCC and exploit them to develop combinatorial treatment approaches especially targeted to NASH-HCC. The overall objectives include interrogation of molecular mechanisms regulating NASH-HCC and the development of novel combinatorial treatment approaches based on the identified molecular abnormalities, evaluation of approaches that improve efficacy of approved immunotherapy using an authentic NASH-HCC mouse model, and development and evaluation of novel approaches that engage the immune system to counteract HCC (inflammatory and NASH-HCC). To achieve this objective, this P01 comprises experts, with an established history of highly integrated interaction, in HCC biology and mouse modeling, liver physiology and pathology, medicinal chemistry, cancer immunotherapy, pathological diagnosis, nanoparticle delivery, and bioinformatics and biostatistics. Successful completion of the proposed studies will significantly advance our understanding of the molecular mechanism of HCC pathogenesis and novel therapeutics and generate translationally relevant data from pre-clinical models having the potential to radically transform the management of HCC patients facilitating prolonged survival. Thus, this innovative P01 grant has high mechanistic and translational significance. ELEVATE brings together the expertise of a highly integrated team providing synergistic outcomes that may not be delivered by each project alone.

NIH Research Projects · FY 2025 · 2024-08

Sphingolipid metabolites are recently emerging as important lipid signaling molecules. Among them, sphingosine-1-phosphate (S1P) is known to play critical roles in cellular processes in various organ systems including kidneys. S1P receptor (S1PR)1, S1PR2 and S1PR3 as well as S1P-producing enzymes are detected in the kidneys. S1P system plays important roles in the pathogenesis of many kidney diseases. However, little is known about the role of the S1P system in renal Na+ excretion. We have recently shown that S1P receptors are prominently expressed in the renal medulla; S1P is a novel diuretic factor in the renal medulla and regulates Na+ excretion via the activation of S1PR1 receptor; S1PR1 in collecting duct is an important antihypertensive pathway by promoting sodium excretion and that impairment of renal medullary S1PR1 contributes to salt- sensitive hypertension. These studies suggest important roles of renal S1P system in salt-sensitive hypertension. Our previous studies focused on S1PR1 receptor. Apparently, levels of S1P production would play critical roles in the function of S1P system. However, whether enzymes that produce S1P participate in the control of Na+ excretion and blood pressure has not been investigated. Our preliminary studies demonstrated that among the enzymes that are responsible for the S1P production, acid ceramidase (AC) as the rate-limit enzyme was significantly increased after high salt intake and inhibited in DOCA-salt hypertension. Moreover, infusion of AC inhibitor into renal medulla and knockout of AC in collecting ducts inhibited sodium excretion and increased salt sensitivity of blood pressure. Based on the above information, the central hypothesis is that high salt-induced AC-S1P pathway in the renal medulla is a novel mechanism to promote the excretion of extra Na+ load and that suppression of renal medullary AC-S1P pathway contributes to the development of salt-sensitive hypertension. Mechanistically, we characterized the expressions of candidate transcription factors and found that Activating Protein 2α (AP2A) was increased after high salt intake and present in the collecting ducts. It is therefore proposed that AP2A is the upstream signal to activate the expression of AC. Indeed, our preliminary data showed that transfection of AP2A shRNA into the renal medulla blocked the high salt-induced AC expression and that the high salt-induced AP2A was suppressed in DOCA-salt mice. Three specific aims are proposed. Aim 1: To test the hypothesis that activation of AC-S1P pathway mediates the excretion of extra sodium load and that inhibition of AC-S1P pathway in the renal medulla impairs renal Na+ handling, thereby enhancing salt sensitivity of blood pressure. Aim 2: To test the hypothesis that the deficiency of AC-S1P pathway contributes to the pathogenesis of salt-sensitive hypertension in DOCA-salt model. Aim 3: To determine the mechanisms causing the deficiency of AC pathway: test the hypothesis that impairment of transcription factor AP2A leads to the suppression of AC levels in the renal medulla in DOCA-salt hypertension. The proposed studies will reveal a novel molecular mechanism in renal Na+ handling and provide new insights into the pathogenesis of salt-sensitive hypertension.

NIH Research Projects · FY 2025 · 2024-08

Adults with lower income are at increased risk of heavy smoking, face reduced cessation success, and bear a heavy burden of smoking-attributable morbidity and mortality. For adults who are not yet ready or able to quit smoking, switching to a lower harm, non-combustible nicotine product could reduce exposure to smoke from combustible cigarettes. However, smokers who are not yet ready or willing to quit nicotine use completely are less likely to switch products without understanding that the health risks of nicotine-containing products are not identical but lie along a continuum of risk (COR), where combustible products are most harmful and noncombustible products less harmful. Studies have identified a general lack of knowledge about the relative risks of nicotine-containing products across the population, and evidence suggests that low-income adults may be least knowledgeable. There is still a lack of evidence about COR perceptions among low-income smokers, the effectiveness of educational messages designed to boost COR knowledge, and whether increasing COR knowledge may impact intentions to switch products and reduce combustible product use. This proposal aims to 1) use qualitative methods to assess COR perceptions among low-income smokers, 2) design and test candidate COR educational messages, and 3) investigate the effects of exposure to COR educational messages on COR knowledge, intentions to switch from combustible to noncombustible products, and reductions in combustible product use among low-income smokers. A comprehensive training plan will ensure successful execution of these aims, with four overall goals for the PI during the training period: 1) proficiency in qualitative research methodology, 2) acquire expertise in clinical trial administration, leadership, and methodology, 3) acquire expertise in advanced statistical methods to evaluate the effects of interventions, and 4) develop expertise in designing, optimizing, and testing health communications. Training will be guided by a team of expert mentors with complementary areas of expertise and current, strong collaborative relationships with one another. This research and training will also be supported by the strong training environment at Virginia Commonwealth University, and prepare the PI to successfully lead independent studies focused on reducing the harms of tobacco and other substance use. Modified Specific Aims People with lower income and/or lower educational attainment have more difficulty quitting smoking and high rates of smoking-related morbidity and mortality. While “no tobacco product is safe”, the FDA’s Center for Tobacco products (CTP) recognizes that tobacco products lie along a continuum of risk (COR), with combusted cigarettes being the most harmful to health. Low-income smokers are less likely to accurately perceive the relative health risks of combusted versus non-combusted products than other smokers and are more likely to incorrectly attribute much of the health harm associated with smoking to nicotine. Further, low-income adults who smoke are less likely to use medicinal nicotine or alternative, non-combusted nicotine products, such as electronic cigarettes (e-cigarettes). While educational campaigns about health risks posed by nicotine and tobacco products have been developed, none have focused on low-income adults, who have higher prevalence of smoking. They also have not delivered comprehensive COR information, nor examined whether increasing COR knowledge will result in behavior change among low-income adults. It is essential to specifically assess COR message effectiveness among low-income adults, not only because of their increased risk of tobacco-related disease, but because they face different tobacco marketing environments and advertising than higher-income adults. Studies have examined the effectiveness of general population smoking cessation campaigns, finding that such campaigns may be less effective among low-income adults, particularly in the absence of complementary tobacco control programs or incentives. The inability of current public health education campaigns to increase knowledge about the health risks posed by nicotine and tobacco products among low-income adults is a critical gap that must be addressed. Consistent with FDA CTP’s stated goal of “educating adults who smoke about the relative risks of tobacco products,” this K01 seeks to answer a critical, unanswered question: does increasing the accuracy of perceptions about the continuum of risk (COR) for tobacco products hold promise for reducing the health harms from smoking combusted cigarettes among low-income adults? Phase 1: Develop, test, and refine nicotine COR educational messages to increase accuracy of nicotine/tobacco risk perceptions. We will conduct qualitative interviews with low-income adults who smoke (n=30) to inform the development of a set of relative risk messages. Next, we will use an iterative series of online population studies to refine and test candidate messages varying in content and design attributes, to identify those most likely to be effective in increasing the accuracy of perceptions of the risks of combustible and non-combustible tobacco products among low-income smokers. Aim 1: Assess accuracy of relative risks of combustible and noncombustible nicotine products among low-income adults who smoke and develop 30 COR candidate messages. Aim 2: Optimize candidate COR educational messages developed in Aim 1 via an iterative series of 3 online population studies conducted among low-income adults who smoke (n=500 per study). Refine messages (e.g., content, design, delivery) based on participants’ assessments of the credibility, likeability, and perceived effectiveness of candidate messages. Identify the 4-6 most effective messages to form a final COR messaging module. Phase 2: Investigate the effects of exposure to COR educational messages on nicotine/tobacco risk perceptions and tobacco use behavior. It is crucial to examine the effects of messages on behavior in addition to perceptions and intentions. We will recruit 60 low-income smokers to participate in a pilot randomized controlled trial testing the effects of COR messaging on perceptions, intentions, and use behaviors. After a one-week baseline in which they can purchase their usual brand (UB) cigarettes via a tobacco marketplace, participants will be randomized 1:1 to exposure to the COR messages developed during Phase 1 or control messages. Starting in Week 2, all participants will have access to UB cigarettes, medicinal nicotine products, and noncombustible products in the tobacco marketplace for two weeks. We will assess effects of messaging on product perceptions, use intentions, and reductions in smoking. We will conduct brief qualitative exit interviews to assess reasons for use among participants who purchased any non-UB products. Aim 3a: Test the hypothesis that exposure to COR messaging will increase the accuracy of risk perceptions, increase switch intentions, and reduce cigarettes smoked per day compared to controls. Aim 3b: Examine reasons for alternative product use among study participants. Hypothesis: COR messaging exposure will increase health reasons for trying alternative products compared to controls. Formal training in qualitative research methods, health communications and clinical trials design will build on the applicant’s prior media, policy, and econometric training, resulting in expertise in the underlying principles essential to delivering complex, targeted health communications. This research will inform an R01 proposal focused on effective use of health communication campaigns to reduce smoking and related health risks among adults who use combusted tobacco products.