George Mason University

NIH Research Projects · FY 2026 · 2023-09

Biomedical imaging technology has undergone rapid advancements over the last several decades, producing large volumes of multimodal imaging data that hold great promise as biomarkers for agingrelated diseases such as Alzheimer’s. Current imaging biomarkers are primarily based on specific extracted one-dimensional measures that may not fully capture the richness of imaging data. Utilizing three-dimensional (3D) or higher imaging information directly may facilitate the identification of more effective disease biomarkers to inform diagnosis, prognosis, and treatment. However, this also brings significant challenges, such as analyzing ir-regularly shaped 3D objects, managing high-dimensional and high-resolution data, addressing noisiness and complexity, quantifying uncertainty, and ensuring the interpretability of the results. Our multi-institutional, inter-disciplinary team of investigators will develop efficient statistical learning approaches and scalable computing tools to extract and assess biomarkers from large-scale brain imaging studies. We will also incorporate genetic and clinical information in constructing the biomarkers. Specifically, our proposal comprises five interrelated research aims carried out by investigators with complementary expertise from three institutions. Aim 1 focuses on developing an interpretable model for genome-wide association studies (GWAS) with brain imaging pheno-types and non-visual contextual information. Aim 2 targets to develop novel nonparametric distributed learning methods for analyzing 3D brain imaging data using an innovative domain decomposition strategy to improve computing performance. Aim 3 quantifies the bias effect in image processing and develops inference methods to reveal the underlying signal from brain imaging data and identify significant brain regions among different diagnosis groups. Aims 4-5 aim to develop statistical methods for obtaining and evaluating imaging-adjusted biomarkers for disease diagnosis and prognosis and assess the incremental value of imaging information over genetic biomarkers on diagnosis and prediction accuracy. The efficacy of the methods developed in this pro-posal will be tested by data collected from studies in Alzheimer’s disease and brain sciences. The proposed research will address critical gaps in current biomarker development and analysis by utilizing advanced sta-tistical learning approaches and computing tools to directly utilize the 3D or higher imaging information. This innovative approach holds the potential to provide more effective disease biomarkers, leading to improved accuracy in diagnosis, prognosis, and treatment for Alzheimer’s disease and related dementias.

NIH Research Projects · FY 2024 · 2023-08

Project Summary/Abstract Adolescents (age 12-17) are disproportionally impacted by mental health challenges. Suicide is a leading cause of death among this age group, with rates of psychiatric inpatient service use consistently increasing since the mid-2000s. Youth psychiatric hospitalization can be traumatic for families and the period following hospitalization is associated with increased risk of repeat suicide attempts and rehospitalization. Increased risk during this time may be due, in part, to low rates of follow-up service use. One factor that plays a substantial role in youth service use is parental burden (i.e., difficulties perceived to be caused or exacerbated by a child's psychiatric symptoms). However, research has not yet explored how parental burden is related to follow-up service use in the post- hospitalization period, or how disparities may influence this relation. Familial socioeconomic status (SES) may be particularly important to consider in this context. There exists a myriad of barriers faced by families of lower SES that impact access to and quality of mental health care. The present study seeks to address these gaps using a mixed methods design. The first aim of this study is to investigate the bidirectional associations between parental burden and youth service use over time following discharge from psychiatric hospitalization. The second aim is to examine how SES impacts the longitudinal relations between parental burden and youth service use. The third aim is to compare the lived experiences of 252 mothers with a recently psychiatrically hospitalized adolescent from high and low SES backgrounds, with a focus on perceptions of burden. Broadly, the fellow’s training goals associated with the proposed study and long-term career plans are to: develop comprehensive knowledge of relevant literatures, such as processes of post-traumatic growth and stress in families, health disparities, and culturally responsive care with underserved youth and families; develop proficiency in qualitative, mixed-methods, and advanced quantitative statistical design and analysis; and improve research dissemination skills. This will be accomplished through coursework, attendance at targeted workshops, hands-on research and clinical experience, directed readings, and regular mentorship meetings. With the support of a dedicated and experienced mentorship team, this research study and training plan will set the stage for the fellow’s long term research goal, which is to conduct culturally responsive, trauma-informed, and family-based treatment research.

NIH Research Projects · FY 2025 · 2023-08

OVERALL CORE ABSTRACT George Mason University (GMU) Biomedical Laboratory (BRL) is one of 12 Regional Biocontainment Laboratories (RBLs) established through NIAID support in the early 2000s to serve as Biosafety Level 3 (BSL-3) facilities to conduct cutting edge pathogen research and serve as resources to rapidly address emerging infectious disease outbreaks. The BRL serves as a center for scientific collaboration to 1) generate advanced knowledge of pathogen biology and host interaction mechanisms, and 2) evaluate diagnostics, therapeutics and vaccines. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic exposed critical vulnerabilities to the nation’s BSL-3 research infrastructure, including the GMU BRL facility. GMU learned that there are gaps and opportunities to enhance safe BRL operations management to more effectively face sudden disease outbreaks and support a more robust pipeline of innovations for response to future pandemics. This proposal outlines activities for three cores to enhance the BRL facility, increase high containment training, and provide additional BSL-3 research services for pre-clinical innovation. The GMU RBL will 1) Implement a comprehensive BSL-3 facilities preventative maintenance and upgrade plan to ensure continuity of operations, compliance with federal regulations, and a safe and secure facility; 2) Enhance safety and quality of BSL-3 laboratory practices; and 3) Create two new research cores in high containment. The expanded Microphysiological Systems (MPS) core will enable organ-on-a- chip (OOC) and organoid models for lead optimization, safety assessment, off target effects, toxicity, and efficacy analysis. The Advanced Animal Research (AAR) core will support pre- clinical studies starting with in vivo exposures and countermeasure testing and transitioning to advanced animal imaging, spatial tissue, and cellular analysis. Together, the cores will accelerate vaccine and therapeutic drug discovery and improve understanding of the transmission and pathogenesis of infectious agents as well as host response.

NIH Research Projects · FY 2026 · 2023-08

Project Summary Extracellular vesicle mediated epigenetic silencing of HIV in the brain Human Immunodeficiency Virus type 1 (HIV) is a lentivirus that causes a persistent viral infection and results in the demise of immune regulatory cells. Clearance of HIV infection by the immune system is inefficient, and integration of provirus into the genome of host cells provides a means for long-term persistence and latency which require lifelong anti-retroviral therapy. Moreover, it is becoming apparent that HIV-infected monocyte/macrophages represent a sanctuary for HIV-1 in central nervous system (CNS), where they appear to contribute to HIV-associated neurological disorders (HAND). A methodology that can specifically target and epigenetically silence HIV provirus within virus infected microglial cells in the brain could be one means by which to develop a functional cure and possibly a treatment for HAND. We recently developed a zinc finger epigenetic repressor that can epigenetically silence HIV in the brain when delivered by extracellular vesicles (EVs) intravenously. We propose here to contrast this recombinant zinc finger approach EV approach with a small hairpin RNA (shRNA) EV approach, which is also targeted to the LTR to epigenetically silence HIV transcription. The premise of this proposal is that cellular-derived EVs can be used to deliver novel anti-HIV zinc finger or LTR targeted transcriptional modulating shRNAs to the brain and epigenetically silence HIV. We propose 3 aims here to test the hypothesis that cellular derived receptor targeted EVs containing anti-HIV zinc finger and the LTR directed shRNA, both regulators of HIV transcription that utilize endogenous cellular epigenetic silencing mechanisms (3-5, 14), can spread systemically in vivo and stably silence HIV transcription. We will test this hypothesis here in vivo using a modular extracellular vesicle (EV) delivery approach, whereby by neural stem cells (NSC) will be engineered such that they constitutively generate anti-HIV EVs capable of cell directed stable epigenetic silencing of HIV. If successful the approach outlined here may not only result in the epigenetic silencing of HIV in the brain but also help usher in a new generation of EV-RNA therapies that can operate seamlessly with endogenous cellular mechanisms to target epigenetic regulation of gene transcription.

NIH Research Projects · FY 2024 · 2023-07

Tumor metabolic reprogramming is a hallmark of cancer progression, survival, and therapeutic resistance. A targetable class of cancer metabolic adaptation exploits mitophagy, a specialized autophagy pathway known to be linked to the cancer phenotype. Mitophagy selectively eliminates dysfunctional mitochondria by targeting them, via autophagosome shuttling, to the lysosome for degradation. Cancer cell mitophagy is triggered by elevated oxidative stress and mitochondria DNA damage caused by hypoxia, radiotherapy, molecular therapy, and immunotherapy. A high mitophagy demand can overwhelm the lysosome capacity resulting in the accumulation of damaged mitochondria that is harmful to the cell, and can suppress biogenesis of healthy mitochondria. We hypothesize that the newly discovered process of secretory mitophagy exports damaged mitochondrial fission-released segments to reduce the overload pressure on the lysosomal system, and thereby sustains cancer cell survival in the face of therapeutic mitochondrial stress. We have discovered a form of secretory mitophagy occurring in vivo in a growing solid tumor. Our molecular analysis of the full repertoire of extracellular vesicles (EV) shed into the resident tumor interstitial fluid (IF) in vivo yielded a rich set of information about the functional state of mitochondria within the tumor cells, and the host cells. Within tumor interstitial fluid, and within the culture media of cancer cells undergoing oxidative stress, we identified an EV-packaged full set of mitochondria molecules comprising the peripheral fission pinched-off segment of the mitochondrial organelle. It has recently been found that peripheral mitophagy fission, regulated by mitochondrial fission 1 protein (FIS1), is a key essential regulator of mitophagy, and is distinct from mid-zone mitochondria fission associated with mitochondria biogenesis. We also found that mitophagy inducer PTEN induced kinase 1 (PINK1) cleavage status (full length versus cleaved), is prominently reflected in the set of mitochondrial proteins exported within IF EVs, and may constitute a new quantitative measurement tool to monitor the real-time state of tumor intracellular mitophagy. Our findings raise important mechanistic questions, that we will explore in the Aims, concerning the unknown intracellular steps of secretory mitophagy and how the content of the exported EVs reflects the internal mitophagy state. Under Aim 1 we will test the hypothesis that peripheral fission secretory mitophagy is induced by high mitophagy demands that overwhelm lysosomal engulfment, and explore if secretory mitophagy is distinct from secretory autophagy within the murine 4T1 and human MDA-MB-231 triple negative breast cancer cell lines. Under Aim 2 we will test the hypothesis that the ratio of full length to cleaved PINK1 is elevated (mitochondria damage sensor) within the exported murine syngeneic breast tumor interstitial fluid EVs, following treatment with mitophagy inducers Mito-CP and Rapamycin. The outcome is new understanding of the importance of secretory mitophagy that can constitute an important therapeutic target, and a new clinically relevant means of monitoring the in vivo state of mitophagic flux within the tumor microenvironment.

NIH Research Projects · FY 2026 · 2023-07

Project Summary/Abstract Adolescence is a risk period for increases in substance use (SU). Also, SU rates are increasing for adolescent girls, however sex differences in SU are under-studied. Given the public health problem of adolescent SU, it is critical to identify risk factors for SU and use those to develop accessible gender-sensitive SU preventions. One risk factor for SU is maladaptive parenting. Maladaptive parenting may lead to lead SU through its effects on adolescent emotion and reward-related arousal. My NIH-funded line of developmental research, using laboratory and fMRI methods, has found that maladaptive parenting predicts heightened negative emotional arousal for girls and heightened reward arousal for boys, which predicts increased SU (R01-DA033431). However, these lab/MRI findings are limited in that they do not capture real-world proximal associations among parenting, arousal, and SU. My other line of research has found that interventions that improve parenting can prevent adolescent SU (R01-DA052427). However, parenting interventions are limited in that they are not accessible to all parents and do not address momentary real-world parenting. To address this, the proposed K02 Award would provide me with protected time (through release from teaching and administrative duties) and advanced training in momentary science to transform my lines of developmental and intervention research and to transform those scientific fields. The K02 would provide me with hands-on training in conceptual models of ecological momentary assessment (EMA), EMA collection and analyses, fMRI-EMA analyses, sensor integration, and ecological momentary intervention (EMI) development. With this training, I will more fully characterize sex differences in mechanisms of parenting effects on SU and will identify targets for accessible smart-phone delivered momentary parenting-focused interventions to prevent SU. The K02 study would add a 4 week EMA of parenting, adolescent emotion and reward arousal, and SU to my ongoing lab/MRI R01 study with a subset of 75 adolescents at their 3 year follow-ups (at age 15-16, during escalation of SU). I will use this EMA to understand momentary parenting, arousal, and SU associations (by sex) in real world contexts. I will leverage already collected fMRI data from the R01 when youth were age 12- 13 to examine whether adolescents’ earlier fMRI responses moderate momentary EMA associations. This K02 Award would enhance my research by allowing investigation of interplay between neurobiological risk and sensitivity to momentary real-world parenting behaviors. The K02 study will benefit from the already recruited and MRI scanned youth in the R01 study who are being followed through the R01 for 3 years with extensive longitudinal assessments. The K02 Award will allow hands-on training in EMA to transform my program of research, pilot data for a R01 application to conduct a large EMA-fMRI study, and training and pilot data for me to develop momentary interventions that reduces negative parenting (or adolescent arousal in response to parenting) in the moment in real world settings to prevent adolescent SU.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY/ABSTRACT Mental health disorders are common, chronic, and costly health conditions for individuals, families, and communities. Treatment options are available, but treatment is underused with less than 50% of adults and 20% of children with mental health disorder receiving treatment each year. There are myriad reasons for not receiving treatment. A potential barrier that has received limited research attention is the time required to receive mental healthcare, which can be time consuming. Time constraints are likely salient for the employed, who much schedule mental healthcare appointments – either for themselves or their dependents – around work hours. The U.S. is one of three industrialized countries that does not have a federal policy that allow employees to take paid time off to attend to healthcare needs of themselves and their families. As of July 2021, 14 states and 21 cities have adopted paid sick leave (PSL) mandates that confer on average 7 days of PSL per year, mandated PSL can be used for mental healthcare. There is strong public support among Americans for PSL, 84% support PSL, and states and localities continue to adopt PSL mandates. The long-term objective of our proposed research is to assist in optimal design in public health policies that allow employees and their families to receive valuable mental healthcare and improve mental health. Specifically, the immediate objective of our application is to use rigorous quasi-experimental methods (e.g., difference-in-differences methods) and high quality, reproducible data (both insurance claims and survey data) to estimate the causal effect of PSL mandates on i) access to PSL among employees with mental health disorders, ii) use of mental healthcare among employees and their dependents (e.g., children and partners), and (iii) indicators for potential quality of mental healthcare received. We will study the extent to which community-level factors (mental healthcare workforce infrastructure, race/ethnicity, and socioeconomic status) mediate the causal effect of PSL mandates on our outcomes. Our data sources are IBM Marketscan commercial claims and the National Health Interview Survey. We will perform analyses separate for adults and children, using variation from all state and city PSL mandates through 2022. A rationale for our proposed research is that mental health disorders are leading causes of morbidity and mortality in the U.S. and use of mental healthcare are below recommended levels and PSL mandates are currently being adopted across the country, raising the importance of understanding how PSL can be used to remove barriers to treatment. Our project is significant by providing new information on the benefits of mandating PSL and potentially removing an under-studied, but empirically important, barrier to treatment: time.

NIH Research Projects · FY 2025 · 2022-09

Research Project Long-Term Objectives: Characterize phenotypic & brain factors related to co-occurring depression & anxiety in adults with autism spectrum disorder [ASD] without intellectual disability, with a focus on an understudied population that is at elevated risk for these conditions: ASD biological females. Results will inform biomarker identification for comorbid depression & anxiety in ASD. Overall research design: 3 samples of ASD young adults (18-30y) will be examined. All samples share phenotyping measures; 2 samples have a common magnetic resonance imaging [MRI] protocol: i) ASD biological males and ASD biological females will undergo phenotyping & MRI; ii) ASD biological males and ASD biological females will undergo phenotyping and ecological momentary assessment [EMA]; iii) existing phenotyping & MRI dataset that of ASD biological males and ASD biological females. Aim 1: Delineate impacts of emotion identification/awareness (alexithymia) & emotion regulation [ER] on depression & anxiety, and role of biological sex in these impacts. Methods: multi-level modeling of EMA-collected depressive/anxious symptoms will examine alexithymia as a cognitive factor in depression/anxiety, and its association with ER. Aim 2: Delineate brain networks associated with alexithymia & impacts on depression/anxiety/ER. Methods: regression modeling will relate structural & functional MRI brain connectivity metrics to alexithymia, ER & depression & anxiety. Health Relatedness: ASD adults experience depression & anxiety at elevated rates, and relatedly, ASD adults show alarmingly elevated levels of suicidality. There is no good understanding of why this is, and relatively little research on mechanisms—including cognitive and neural factors—that predispose ASD adults to these serious mental health conditions. This project thus seeks to idenfity potential mechanisms of elevated risk and advance solution-oriented approaches in health disparities research of autistic adults. Candidate’s Career Goals & Development Plan: Dr. McQuaid’s long-term goal is to become an independent investigator with a research program focused on ASD in adulthood and factors relevant to improving mental health in this population. Her short-term goals are to characterize brain & behavioral/cognitive factors that predict increased vulnerability for depression & anxiety in ASD. Building on her multidisciplinary background, Dr. McQuaid will receive training in 1) ASD & measurement of mood/anxiety in ASD; 2) EMA & computing skills; 3) professional development & open science practices to support and further her commitment to replicable, reproducible and generalizable research. Environment: Dr. McQuaid is supported by a cohesive team of expert scientists with overlapping & complementary research programs. They will provide an intensive, focused, & seamless mentorship experience, and their expertise & institutional affiliations will provide Dr. McQuaid with the guidance & resources to achieve the research aims & training goals. Taken together, the research & training, mentor team, & environment afforded by the K01 will serve as a bridge that will successfully transition Dr. McQuaid from her current position to that of an independent investigator.

NIH Research Projects · FY 2023 · 2022-08

PROJECT SUMMARY/ABSTRACT: Blood-contacting medical devices, such as stents and heart valves, are common treatments in modern healthcare. Every year, approximately 1 million and 90,000 stent and prosthetic heart valve procedures are performed in the US, respectively. However, the use of these devices is associated with substantial risk of thrombosis, and the rate of failure due to clot formation can be as high as 6%. When whole blood plasma comes in contact with a foreign body (e.g., an implant), it leads to four main events capable of inducing a thrombogenic response in vivo: protein adsorption, platelet adhesion/activation, leukocyte recruitment, and further activation of complement and coagulation. Within seconds to minutes, key blood plasma proteins are adsorbed and undergo conformational changes on the surface. This layer of adsorbed protein will allow subsequent adhesion and activation of platelets, which promotes the formation of the fibrin clot, as well as the recruitment of leukocytes. The platelets then initiate an inflammatory immune response and promote a complex cascade of events resulting in thrombosis and/or fibrous encapsulation of the implant. Due to this complex foreign body response, hemocompatibility has been a significant issue for blood-contacting medical devices. To address this challenge, the development of novel biomaterials that can appropriately interact with blood and prevent thrombosis is vital for the success of many implantable devices. In this work, we propose to prevent thrombosis on implants by combining the promising properties of two biopolymers with nanoscale features on titania to develop a novel blood-compatible surface. Biopolymers are good candidates for these applications, because of their compatibility with the human body, biodegradability, processability and, in some cases, inherent antifouling and antithrombogenic properties. Our preliminary results indicate that carboxymethylation of kappa-carrageenan with monochloroacetic acid to form carboxymethyl-kappa-carrageenan (CMKC) improves the antithrombogenic properties. CMKC is chemically similar to heparin and prevents thrombosis through multiple mechanisms. However, CMKC is derived from algae, a renewable and low-cost source, while heparin is obtained from animal tissues. Moreover, CMKC does not cause the side effects that heparin presents, such as bleeding effects. Our group also has recently used of tanfloc (TA), a condensed tannin polymer as a biomaterial, and we have demonstrated its promising cytocompatibility, antioxidant activity, antimicrobial, and antifouling properties. Previous studies done by our group showed that the modification of titanium surfaces with TA and heparin decreased the blood protein adsorption/activation, and platelet adhesion and activation. This work aims to combine these promising properties of both biopolymers (CMKC and TA) to develop novel surfaces on titanium that can prevent thrombosis.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY/ABSTRACT Bacterial biofilms are responsible for most human infections, causing tens of thousands of deaths and billions in medical costs per year. Topical biofilms alone cause significant harm to patients by growing on open wounds, skin lesions, burn injuries, or diabetic ulcers, and elsewhere. Biofilms are notoriously difficult to eradicate, in large part because of the extracellular polymeric substance (EPS), a self-produced extracellular matrix in which biofilm bacteria reside. The EPS benefits bacteria in many ways, including mediating quorum sensing, providing nutrients, and blocking transport of antibiotics and host immune response. The ability to actively penetrate the EPS and deliver anti-bacterial cargo where it is most needed would bypass many of these protections and could thus have a transformative impact on the remediation of biofilms. First introduced in 2004, artificial self-propelled particles (SPPs) can propel themselves through complex biological media and deliver cargo to specific locations. Thus, SPPs hold significant potential for biomedical applications such as biofilm remediation. However, SPPs must overcome significant challenges in the form of biocompatibility, tracking, and control to be viable for clinical use. Here, we propose to leverage the burgeoning field of DNA nanotechnology to develop urease-powered DNA-origami-based self-propelled particles (DNA-SPPs) for biofilm remediation. As a model organism, we focus on the well-studied pathogen Pseudomonas aeruginosa. Aim 1 of this study will quantify the dependence of DNA-SPPs’ locomotion on local urea concentration and pH and elucidate the extent to which they perform chemotaxis in urea gradients. Aim 2 will test the hypothesis that if DNA-SPPs are decorated with glycosyl hydrolase enzymes (which are widely used to disrupt the biofilm matrix, specifically in the case of P. aeruginosa), they will degrade the biofilm matrix as they move through it, weakening the protection the EPS normally provides to bacteria. The success of Aim 2 will be marked by greater efficacy of a model antibiotic (ceftazidime, which has demonstrated efficacy at treating P. aeruginosa biofilms) administered topically. In Aim 3, we will load ceftazidime directly onto DNA-SPPs using a pH-sensitive motif (e.g., I-motif) that undergoes structural changes in response to pH decrease, thus releasing cargo only in acidic regions. By correlating the delivered payload to the pH distribution, we will confirm the ability of DNA-SPPs to deliver cargo preferentially in acidic regions, where hard- to-reach bacteria tend to cluster. Finally, we will assess the combinatorial benefits of the approaches in Aims 2 and 3 by using DNA-SPPs to both increase the biofilm’s permeability and to deliver antibiotics deep inside the biofilm. The major output of this study will be design criteria for DNA-based enzyme-powered SPPs to disrupt and deliver cargo in extracellular matrix (ECM) environments, which could have a major impact on the treatment of biofilms, and will lay the foundation for a customizable platform technology applicable to a wide range of ECM- mediated diseases.

NIH Research Projects · FY 2025 · 2022-03

ABSTRACT My goal in pursuing a Mentored Research Career Development Award is to gain the necessary training, knowledge, and practical experience needed to become an independent investigator focused on improving access to and utilization of PrEP among Black men who have sex with men (BSMM) through social, peer- based intervention research. To continue my progress towards my career goals, I propose to conduct an intervention focused on increasing PrEP acceptability through developing and maintaining peer support and resilience to intersectional racism and homophobia among BSMM in Prince George’s County, MD. Despite a clear, well-documented need for greater uptake of PrEP among BSMM in this county, PrEP uptake among BSMM in this setting remains low, and extant literature specific to PrEP use in this setting and population is extremely limited. To address this need, I propose the following: Specific Aims: 1) Understand peer-peer interactions/exchanges and HIV prevention communications among BSMM through ethnographic qualitative observations (participant and direct) of two ongoing MPowerment models, 2) conduct qualitative in depth interviews to inform designing an intervention to reduce internalized racism, internalized homophobia and increase PrEP initiation among BSMM in PG County, and 3) pilot test a community-based intervention (130 participants) to reduce internalized racism, internalized homophobia, and HIV stigma and increase social support and PrEP initiation among BSMM in PG County, based on the MPowerment model. In addition to my specific aims, my Specific Career Development Aims are the following: 1) To develop expertise in the analysis of qualitative data, particularly related to social and structural factors, 2) to develop expertise in the collection and analysis of network data collected via respondent driven sampling, 3) to gain experience in the design, conduct, and evaluation of interventions and 4) to develop research management and professional development skills needed to lead future independent research projects. The knowledge and experience gained from the proposed research will provide me the skillset necessary to successfully compete for R01 funding to conduct a larger scale peer-focused intervention to promote PrEP acceptability and adherence among BSMM. The proposal makes significant contributions to the field in several ways, including 1) identifying barriers to PrEP acceptability among BSMM in Prince George’s County, 2) Qualitatively understand factors that may impact observed quantitative associations between barriers and PrEP use and acceptability, and 3) developing and evaluating an MPowerment intervention to improve PrEP use and acceptability in this population. My rigorous education, training, and research experience in social determinants of HIV/STI risk, collaborations with BSMM populations and organizations, proficiency with quantitative data analysis, and the expertise of my multidisciplinary research team, uniquely prepares me to conduct the proposed research and significantly contribute to HIV prevention science.

NIH Research Projects · FY 2025 · 2021-07

Project Summary/Abstract Substance use disorders (SUDs) are a significant public health problem. There is a need for novel substance use prevention strategies for adolescents, particularly developmentally-informed interventions rooted in basic science findings. Significant basic research indicates parent stress as a risk factor for adolescent substance use. A separate body of research finds that mindfulness interventions reduce stress in adults. Taken together, mindfulness interventions may reduce parent stress and prevent increases in substance use in adolescence. However, few randomized controlled trials (RCTs) have evaluated mindfulness interventions for parents and none have tested neurobiological mechanisms. Through our NIDA-funded R34 (Pilot and Feasibility) award, we developed and conducted a pilot RCT of a parenting-focused mindfulness intervention, the Parenting Mindfully (PM) intervention, in 100 highly-stressed parents of adolescents. We found that PM reduced parent stress, increased adaptive and mindful parenting behavior, decreased parent emotional and cortisol stress reactivity in our laboratory parent-adolescent interaction task (PAIT), and prevented increases in adolescent substance use and psychopathology symptoms to 1 year follow-up, as compared to a Parent Education (PE) control. In a sub-sample of 20 mothers, PM also decreased mothers’ anterior insula reactivity and increased amygdala to dorsolateral prefrontal cortex connectivity, which predicted more adaptive parenting. The proposed study will take the next step by conducting a large RCT of PM with a longer follow-up and more rigorous PE control and by fully testing neurobiological mechanisms. 300 highly-stressed parents of early adolescents (age 12-14) will be randomly assigned to receive the PM or PE intervention. Before, during, and after the interventions, and at 6 month, 1 year, and 2 year follow- ups (into middle adolescence), we will collect questionnaire, clinical interview, and biological measures of parent stress, parenting, adolescent substance use and substance use problems, and adolescent (and parent) SUD and psychopathology symptoms. At pre- and post-intervention, observed adaptive and mindful parenting behaviors and parent emotional and cortisol stress reactivity will be measured in the PAIT task. 150 mothers will complete fMRI sessions at pre- and post- examining emotion-related neurobiological mechanisms. We will examine: 1. Efficacy of PM in preventing increases in adolescent substance use and symptoms; 2. Parent stress and parenting as mechanisms of PM on adolescent substance use; 3. Parent emotion-related fMRI responses and connectivity as neurobiological mechanisms of PM. This will be the first RCT of a stand- alone mindfulness intervention for parents of adolescents and the first to test neurobiological mechanisms. The study will provide an effective intervention to both reduce parent stress and prevent youth substance use and will identify neurobiological mechanisms to target and strengthen PM and other parenting interventions.

NIH Research Projects · FY 2024 · 2020-09

ABSTRACT Venezuelan equine encephalitic virus (VEEV) infects humans and is classified as a Category B pathogen by NIAID due to its easy dissemination. In humans, VEEV infection can result in inflammation, acute degenerative neuronal changes, behavioral changes, memory loss and seizures, with severe cases resulting in death. There is currently no antiviral therapeutic treatment for patients infected with VEEV. The live attenuated vaccine TC83 can protect against VEEV infection, but due to a high frequency of adverse side effects, its use is limited to military and at-risk laboratory personnel. Therefore, the discovery of new therapeutics is urgently needed. VEEV is able to suppress host transcription by blocking cellular nuclear trafficking at least partially due to its capsid protein forming a complex with the host proteins importinα/β (Impα/β1) and CRM1. Mutation of the nuclear localization sequence (NLS) of capsid results in loss of viral virulence, indicating that the ability of capsid to enter the nucleus is critical for VEEV pathogenesis and a viable target for antiviral therapeutic development. We hypothesize that small molecule inhibitors that interfere with capsid-Impα protein-protein interaction (PPI) will prevent VEEV induced pathologies. We have identified two novel small molecules, 1111684 and G281-1485, which disrupt the ability of VEEV capsid to interact with Impα, leading to altered capsid localization, decreased viral replication and increased survival of the host cell. Here we propose to design and synthesize second- generation capsid-Impα PPI inhibitors with improved potency and bioavailability. To this end, we proposed 4 interlinked aims: Aim 1: In silico design of second-generation capsid-Impα inhibitors; Aim 2: Synthesis and biochemical characterization of second generation capsid-Impα inhibitors; Aim 3: Determine the in vitro selectivity index and bioavailability of capsid:Impα inhibitors; and Aim 4: Determine the PK/PD/Tox of capsid:Impα inhibitors. The new knowledge gained from our study will be applicable to wide-range applications involving capsid-Impα interactions including HSV-1 or eastern and western equine encephalitic viruses.

NIH Research Projects · FY 2025 · 2020-08

This proposal is to develop a new senior year capstone design course and summer immersion program for Bioengineering students at George Mason University. Recognizing the importance of introducing the biomedical design process early and building on this throughout the undergraduate program, our Bioengineering Department has introduced a new curriculum where design is taught in each of the four years. The curriculum begins with an introductory Computer-aided design based experience in the freshmen year, followed by a biomaterials design project in the sophomore year and a course with a product development component in parallel with a course in clinical medicine (taught by physicians) in the junior year. The new proposed capstone design course builds upon this foundation beginning with a summer clinical immersion program that leads into an analysis phase of identified clinical needs in the capstone design course. To further support our design teams in addressing patient-oriented clinical needs and emerging opportunities involving health informatics and health policy, we will include a senior student from nursing, health informatics or health policy into each design team, based on a skill set analysis of each project. The design teams are supported by advising teams composed of faculty from Bioengineering, Nursing, Health Informatics and Health Policy and by industry advisors selected from our new industry advisory board, the Mason Bioengineering Alliance. Design teams will have access to university and medical center resources and follow an industry standard product design and development process. Our approach includes a practical early stage assessment of clinical importance and market potential including the important aspects of intellectual property, regulatory considerations, ethics and reimbursement. This proposal aims to 1) establish a multidisciplinary summer clinical immersion program leading into the Bioengineering capstone course at 3 clinical centers : Inova Fairfax Medical Campus, Children’s National Medical Center and Georgetown University Medical Center 2) integrate Nursing, Health Informatics, and Health Administration students and faculty into Bioengineering Design teams (students) and advisory groups (faculty) and 3) apply in a real world clinical context our new curriculum’s foundation of multiyear design and courses in i) Clinical Medicine and ii) Intellectual Property, Regulatory Concepts, Product Development, responding to newly identified clinical needs. A design control approach with inclusion of relevant standards and risk analyses are included. Workshops will teach ethics, reimbursement and oral communications. Using this integrated, translational approach to learn design will better prepare our students to be biomedical technology innovators. Incorporating a clinical needs finding approach and working with health professional students involved in patient care and health administration will give our students a unique real world experience in patient-oriented bioengineering design. With this senior design course under their belt, our students will be prepared for industry positions, for starting their own companies, or for further graduate education. 1

NIH Research Projects · FY 2025 · 2019-09

Individuals involved in the criminal legal system (CLS) are at greater risk for overdose than the general public. This renewal proposal is for the JCOIN 2.0 Coordination and Translation Center (CTC), designed to advance use of scientific knowledge on effective policies, practices, and programs in legal, community, and/or health settings. The proposed CTC team successfully established and executed the JCOIN 1.0 CTC. Core leaders in health-legal research and practice disciplines include Faye S. Taxman, Amy Murphy, and Judith Wilde (Mason), Jessica Hulsey (Addiction Policy Forum), Danielle S. Rudes (Sam Houston State University), Todd Molfenter (University of Wisconsin-Madison), and Carrie Pettus (Wellbeing & Evaluation Innovations). Our expertise covers the legal system including deflection (Taxman, Pettus, Henderson); pretrial, courts and adjudication (Taxman, Pettus, Murphy, Wilde); institutional corrections and jails (Taxman, Rudes, Pettus, Molfenter); community corrections (Taxman, Rudes, Pettus, Murphy, Molfenter); policing (Taxman); prosecution and defense (Pettus); community treatment (all), to name a few. The team is committed scholars and practitioners with diverse disciplines and geography. The CTC goals are: Aim 1: Dissemination to reduce the translational gap in legal- health-community organizations; Aim 2: Meaningful stakeholder engagement and collaboration; Aim 3: Expanded outreach and capacity building to workforce, students, practitioners, community organizations; and Aim 4: Implementation to reduce the translational gap. In JCOIN 1.0, this CTC engaged researchers, practitioners, and families to access research that can improve the delivery of prevention and treatment policies, practices, and programs. We had many successes including a website with over 240,000 page views, 65 original eCourses and webinars that reached over 6,300 course enrollments, and four seasons of the Aced It podcast with 11,000 downloads. In JCOIN 2.0, the CTC will further efforts aimed at conducting outreach, disseminating information, co-production with stakeholders of materials and products, conducting spread and scale-up studies, funding 14 grants, and developing the workforce and early career researchers on JCOIN-related studies. Innovations include adding to the External Advisory Panels; translating JCOIN-related research findings into actionable steps, testing the Implementation Translation Spread and Scale-Up (I-TranSS) framework in five or more low-cost studies, funding 14 grantees, expanding LEAP to 40 scholars and 40 investigators, providing TA to fulfill 100 requests or more, expanding JTEC for target audiences, and prioritizing health as part of translation, dissemination, and implementation efforts. The CTC is energized to set new records on translation and dissemination to health and justice audiences and impact the uptake and penetration of JCOIN and other HEAL- funded studies into everyday practice. There are minor changes to the aims to ensure compliance with 2025 Executive Orders.