Washington University

NSF Awards · FY 2024 · 2024-08

Quantum technologies are poised to make significant impact in many areas of science and technology with applications in national health, industry, and defense. These technologies harness the unique properties of quantum superposition and entanglement to achieve tasks in a more efficient manner or in ways that are fundamentally impossible without quantum technologies. One of the nearest-term applications of quantum technologies is in the realm of quantum sensors. This project focuses on developing new types of quantum sensors that are enabled by quantum entanglement; they achieve an advantage over more classical sensors that do not harness this powerful quantum property. The project applies these sensors in the domain of open quantum systems, which seeks to find ways to understand and harness dissipation in quantum technologies. In this way, the project aims to demonstrate new quantum sensors, while also advancing quantum technologies broadly. In addition, the project will train undergraduate and graduate students in quantum information and quantum sensing techniques. The project focuses on three key projects. The first project aims to leverage an entanglement-enabled probe to characterize memory’s role in quantum systems’ environments, investigating how entangled states can form an enhanced probe of the non-Markovianity of an environment. We plan to apply this probing technique to characterize a range of different decohering mechanisms in open quantum systems. The second project investigates new approaches to quantum-entanglement-enhanced metrology harnessing time reversal invariance. Here, we will utilize the entanglement between a probe and an ancilla to perform optimal sensing of unknown and fluctuating magnetic fields. The third project will investigate a transition between quantum and classical dynamics by manipulating a qubit array via quantum measurement. The project will advance the scale of quantum simulation efforts with superconducting qubits and continue to demonstrate how dissipation serves as a powerful resource for quantum simulation. 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 · 2024-08

Despite advancements, about 700,000 people in the U.S. still experience an ischemic stroke annually. Current treatments for acute ischemic stroke are largely restricted to thrombolysis or thrombectomy, for which many stroke patients are ineligible for. Therefore, developing novel therapies for stroke is a significant public health need. Understanding the cellular mechanisms underlying stroke is critical for the development of new stroke therapies. Neutrophils and platelets are critical regulators of ischemic stroke injury. In humans and mice, platelet-neutrophil aggregates increase after ischemic stroke as well do neutrophil extracellular traps (NETs), a marker of neutrophil activation. NETs are critical during inflammation and infection and are released by neutrophils to trap pathogens. While NETs help fight infection, excessive NET formation can be detrimental to the host by promoting thrombosis. However, the pathological role of NET release has not been studied in ischemic stroke injury. Furthermore, the molecular regulators that trigger NET formation during stroke remain unclear. Finally, if targeting NET release during ischemic stroke injury improves outcomes is completely unknown. Here, we will test the innovative hypothesis that platelets are a primary driver of NET release during ischemic stroke and targeting NET formation with a novel, endogenous NET- inhibitory factor (nNIF), will improve stroke outcomes. We will employ complementary clinical, in vitro, and in vivo approaches, along with state-of-the-art techniques and models to rigorously test this hypothesis. Specific Aim 1 will determine if NETs are released after ischemic stroke and if they are present in the brains of human stroke patients and mice after experimental stroke. Furthermore, we will examine if neutrophils are primed to release NETs in ischemic stroke patients. Specific Aim 2 will establish whether platelet high mobility group box 1 (HMGB1), a danger associated molecular pattern released by platelets after activation, regulates NET formation during ischemic stroke injury. Specific Aim 3 will determine if therapeutic nNIF administration blocks NET formation during experimental stroke and improves acute and long-term stroke outcomes, including motor and neurological function. Successful completion of these aims will 1) determine if NETs are present in ischemic stroke injury including intravascular and extravascular locations; (2) establish whether neutrophils and platelets are primed to participate in NET formation during ischemic stroke, (3) determine whether platelet HMGB1 is a critical regulator of platelet-mediated NETosis during ischemic stroke; and (4) determine if NET inhibition improves stroke outcomes and the therapeutic window associated with pathological NET formation. Data generated in this proposal will significantly increase our understanding of how platelets contribute to pathological NET formation during ischemic stroke and associated neurological injury.

NIH Research Projects · FY 2026 · 2024-08

ABSTRACT Suboptimal health outcomes are common among older adults living with Alzheimer's Disease (AD) and AD-related dementias (ADRD). One way to improve outcomes in Medicare is by moving beneficiaries into accountable care organizations (ACOs), in which groups of clinicians assume responsibility for quality and costs of care for patient populations on an annual basis. In 2023, the ACO REACH program was launched. This new program differs from Medicare's current ACO program (the Medicare Shared Savings program, or MSSP) in that it includes features and considerations specifically aimed at providing additional flexibilities in care delivery that could help people with AD/ADRD, including home-based care waivers and global payments. Quantifying the impact of ACO REACH is critically important as Medicare and other payers increasingly shift towards ACO programs. Our overarching goal in this proposal is to determine if ACO REACH improves health outcomes, overall and among beneficiaries with AD/ADRD, compared to Medicare's current ACO program (the Medicare Shared Savings program, or MSSP) or to beneficiaries not enrolled in an ACO program. We also hope to understand the specific care redesign strategies ACOs undertake that might have particularly beneficial effects for people with AD/ADRD, using an implementation science lens to explore these in detail. Our specific aims are as follows: • Aim 1: Compare REACH ACOs to MSSPACOs and non-participants on beneficiary, practice, and organization-level characteristics over time to determine whether ACO REACH is achieving its goal of enrolling practice groups that have not previously joined ACOs. • Aim 2: Use innovative within-beneficiary analyses to determine if ACO REACH is associated with improvements in quality and outcomes, overall and among beneficiaries with AD/ADRD. • Aim 3: Use an implementation science framework and a series of longitudinal interviews to characterize ACO REACH leaders' decision-making around program participation, practice engagement, quality improvement, and health outcomes, overall and for beneficiaries with AD/ADRD. This work will provide timely information to inform ongoing updates to ACO REACH, and ways in which its implementation could be further optimized for patients with AD/ADRD. This could help to maximize the likelihood that ACO REACH and future programs will have meaningful positive impact on all populations living with dementia.

NIH Research Projects · FY 2025 · 2024-08

Abstract Prostate cancer (PC) is one of the leading cause of cancer deaths among American men. Advanced PC patients often receive androgen deprivation therapy, but, the recalcitrant disease recurs within 2-3 years, referred to as the Castration Resistant Prostate Cancer (CRPC). Androgen Receptor (AR) antagonists such as enzalutamide (Enz) or abiraterone (Abi) are currently favored therapeutics for PC patients, however, virtually all patients develop resistance. Post-CRPC state, therapeutic options for the recurrent disease are limited. We discovered a non-receptor tyrosine kinase, ACK1, as a novel epigenetic modifier in prostate tumors, regulating AR/AR-V7 expression. Enthused with these data, we developed a new class of ACK1 small molecule kinase inhibitor, (R)-9b. (R)-9b inhibits ACK1 and downregulates AR and prostate specific antigen (PSA) expression to suppress prostate xenograft tumor growth. Moreover, in immune competent mouse models, (R)-9b induces significant CD4+ and CD8+ T cell activation against syngeneic prostate tumors. Employing ex vivo 3-D assays, we confirmed that (R)-9b functionally reinvigorates peripheral blood mononuclear cells (PBMCs) of the CRPC patients to mount a robust immune response against human CRPC organoids. Together, these data indicated that ACK1 inhibitor, (R)-9b with tumor-intrinsic and tumor-extrinsic activities in the host tumor microenvironments is a novel class of inhibitor with much needed immunomodulatory activity. Prolonged (R)-9b treatment exhibited normal histology suggesting that it is not associated with toxicity, further underscoring the importance of targeting ACK1 to overcome resistance to AR-targeted therapies. We have completed an extensive pre-Investigational New Drug (IND) studies including pharmacokinetic, pharmacodynamic and metabolism studies in mouse/rat/canine models, which revealed that (R)-9b possessed excellent drug-like properties. These data is submitted to FDA (IND#167907). This proposal is directed towards phase I clinical trial for ACK1 inhibitor (R)-9b in CRPC patients to examine its ability to overcome CRPC resistance by cytotoxic and immunomodulatory activity. Specifically, we will: Specific Aim 1: To assess the safety/tolerability, pharmacokinetics, and anti-tumor activity of (R)-9b in CPRC patients Specific Aim 2: To evaluate peripheral blood and tissue markers of anti-tumor and immune response after (R)-9b exposure. Overall, successful completion of this study will open a new therapeutic modality for CRPC patients who have developed resistance for Enzalutamide and Abiraterone, which is a critical unmet need.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Survival from cervical cancer is stagnating in the United States. Despite many intervening clinical trials, the standard of care (SOC) definitive chemoradiation therapy (CRT) has remained unchanged since the addition of concurrent platinum-based chemotherapy to radiation in the 1990’s. Reasons for this are several-fold, and include a patient population that is disproportionately affected by barriers to care, inherent radioresistance of gross disease as evidenced by local recurrence after a mean primary tumor dose of >200Gy delivered with brachytherapy plus EBRT, and insufficient systemic control, with distant failure contributing to two thirds of cervical cancer deaths. A suboptimal immune response at the time of definitive CRT is associated with local, regional, and distant recurrence, as well as death from cervical cancer. We have previously shown that enrichment of immunosuppressive cells and high expression of squamous cell carcinoma antigen (SCCA), known as SERPINB3, are associated with higher risk of recurrence after SOC CRT in cervical cancer, and that CRT induces further infiltration of tumor permissive myeloid derived cells. Preliminary data suggest that tumor associated macrophages, myeloid-derived suppressor cells, and regulatory T cells are increased in mid- treatment tumor specimens from patients undergoing standard CRT. Using preclinical models, we find that brachytherapy stimulated expression of immune-stimulatory signals to a greater degree than an equivalent dose of EBRT. Finally, SERPINB3 directly promotes expression of chemokines that recruit immune-suppressive cells, particularly myeloid-derived sub-populations, blunting the T-cell anti-tumor response in cervical cancer. We hypothesize that brachytherapy alone delivered to the primary tumor prior to regional lymph node EBRT will safely minimize patient trips, further stimulate the immune system, and potentiate the efficacy of immunotherapy. Two aims are proposed to directly test this hypothesis: Aim 1 will determine if accelerated brachytherapy-forward chemoradiation therapy (ABC-RT) is a safe and effective approach to shorten overall treatment time, and maximize anti-tumor immune response through a phase I/II clinical trial for patients with locally advanced cervical cancer. Aim 2 will determine if ABC-RT potentiates the anti-tumor activity of immune checkpoint therapies and/or the myeloid-cell inhibitor CCR2i using a preclinical murine tumor model with a novel intracavitary brachytherapy system developed for this proposal. Secondary endpoints to validate candidate biomarkers SERPINB3, and post therapy FDG-PET as predictors of recurrence after this experimental approach are proposed to precisely stratify patients for subsequent trials incorporating drug-ABC-RT combinations. Success of these aims will provide the preliminary data to support randomized trials of ABC-RT based regimens compared to the SOC and ultimately a paradigm shift in the definitive treatment of cervical cancer. The proposed translational studies will provide a template for integration of therapies that synergize with CRT and the immune response. The overall goal of this proposal is to improve survival for patients with locally advanced cervical cancer.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY In this K24 application, I seek to enhance my capability as a leader in patient-oriented cardiovascular research and mentorship at Washington University. The proposed research includes new advanced implementation research using the NHLBI-funded Hypertension Treatment in Nigeria Program, which I co-lead with Dr. Dike Ojji from University of Abuja and is among the largest hypertension control programs in Africa. Specifically, I seek to understand not just if, but how, why, and in what context implementation of the World Health Organization’s HEARTS technical package improves hypertension care at multiple levels—patient, site, and system. To do so, my research explores multi-level mediation of team based care (the “T” in HEARTS) on blood pressure at site and patient levels, as an exemplar. I also seek to define trajectories of retention, also known as persistence, in longitudinal hypertension care. Based on these results, I will use mixed methods including new patient oriented data collection through key informant interviews and discrete choice experiments to understand reasons and preferences for retention trajectories and re-engagement in care. I will be supported by outstanding dissemination and implementation science researchers at Washington University to advance my own research skillset through these research aims. This proposal also includes the dual goal of improving my mentoring skills. Short-term goals focus on expanding my mentoring of patient oriented clinician investigators for NIH K or similar awards and securing additional R and D grants, as well as new P grants, to support both my research and that of my mentees. Medium- and long-term goals aim to establish a best-in-class mentorship program in global cardiovascular patient oriented research at Washington University in collaboration with the World Heart Federation and to facilitate successful transitions for US and international mentees from K to R-level funding (n=6 currently). I will participate in additional mentorship training, leadership programs, and research skill development activities during the award period, including related to the responsible conduct of research and global health ethics through the NIH-funded Compass program. I will use the Mentor Competency Assessment as a tool to monitor my performance. I will use the NIH-sponsored Translational Science Benefits Model to disseminate my research and will help my mentees incorporate this approach into their own methods. My exceptional mentoring team comprises experts like Drs. Elvin Geng, Victor Dávila-Román, Margaret McNairy, and Dike Ojji, who bring a wealth of relevant experience and skills in advanced dissemination and implementation research, research training programs, global health, and women in global health. We will meet regularly to refine my mentoring strategies and skills. This integrated approach ensures that I can provide top-tier mentoring while generating new, high-impact patient oriented research.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Growing evidence suggests that individuals with Type 1 diabetes mellitus (T1D) are at risk for cognitive dysfunction over time, with approximately 28% of middle-aged adults with T1D and 48% of older adults with T1D meeting criteria for clinically significant cognitive impairment. Our team and others have shown early appearing differences in brain structure and selected cognitive functions, with differing trajectories over time in children with T1D. However, significant variability in outcomes remains unexplained, and there is debate about the mechanisms and modifiable factors contributing to these neurocognitive deficits. Studying early cognitive, functional, and structural effects in young patients with T1D before complications occur is a necessary step towards informing risk factors, critical periods for prevention and intervention, and strategies to mitigate the risk of neurocognitive complications of T1D later in life. Previous work has not been adequately powered or designed to determine the effects of potential modifiable or protective risk factors for brain outcomes, how T1D factors influence dynamic cognitive function in real-world settings and whether individuals with T1D from diverse socioeconomic situations face greater risk for altered brain outcomes. We propose to address these deficiencies by first engaging community stakeholders from diverse backgrounds to better understand families' perspectives and needs. Their input will then guide the specific recruitment and data collection methodology that we employ for this longitudinal study of diverse, prepubertal children with newly diagnosed T1D and their siblings without T1D. In sum, this work will provide a definitive view of the complex risk and protective factors shaping neurodevelopment in a diverse group of children with T1D and will help identify critical targets for intervention to promote optimal brain and cognitive outcomes.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Iron deficiency anemia (IDA) experienced in early childhood causes long-lasting negative consequences on brain development, connectivity and cognition. Given the high prevalence of IDA in infants and toddlers and significant neurocognitive consequences, IDA screening is widely recommended in the first year of life. However, the brain continues to develop throughout childhood, and the incidence of IDA sharply increases again in late-childhood among menstruating females, occurring in 1 of every 16 adolescent females. Of greatest concern, recent studies have found that late-childhood IDA negatively impacts cognitive performance. Anemia results in cerebral metabolic stress with compensatory increases in cerebral blood flow and oxygen extraction fraction. In severe anemia, the compensatory mechanisms may be inadequate to maintain the expected metabolic rate of oxygen utilization (CMRO2), impacting the structural and functional development of the brain. The goal of this proposal is to delineate the short and long-term neurocognitive impact of late-childhood IDA in young females by testing the central hypothesis that late-childhood IDA causes cerebral metabolic stress that contributes to both reversible and potentially irreversible changes in neurocognitive function. Eighty-eight young females between 12-21 years of age with IDA will undergo cognitive evaluation and brain MRI assessing cerebral metabolism and structural and functional connectivity at time of diagnosis, 6 weeks after iron repletion, and at 1-year post-enrollment. Forty-four age-matched females without anemia will be enrolled and assessed at similar time-points for comparison. We will compare cerebral metabolic stress and compromised metabolism between the two groups (Aim 1). A subgroup of females with IDA that receive IV iron therapy will have brain MRIs weekly for 6 weeks post-repletion. Dense imaging of this subgroup will determine the hemoglobin threshold resulting in metabolic failure. The change in functional connectivity and cognitive abilities with resolution of anemia secondary to iron therapy will be measured to assess the potential reversibility of neurocognitive dysfunction with iron repletion (Aim 2). Lastly, cognitive evaluation and brain MRIs one year after enrollment will be used to determine the relationship between cerebral metabolic stress at diagnosis of IDA and long-term integrity of the white matter microstructure as it relates to cognitive abilities (Aim 3). Determining the neurocognitive effects of late-childhood IDA has important implications for potential screening and optimizing therapy recommendations at a time when cognitive performance has life-long implications for educational and career options for young women entering adulthood.

NIH Research Projects · FY 2026 · 2024-08

PROJECT SUMMARY Determining accurate models of the developing brain’s functional architecture during the first two years of life has potential prognostic value for maturation milestones and the onset of psychopathology. A growing body of literature suggests that infant and toddler brain functional connectivity (FC) networks (as defined using functional magnetic resonance imaging; fMRI) are less mature than adult networks. However, there are two distinct and potentially interacting factors present when estimating infant and toddler FC: 1) age and 2) state. Critically, infant and toddler fMRI data are collected during natural sleep, while fMRI data in older populations are typically collected during resting wakefulness. Research suggests that pediatric FC estimated from sleeping state fMRI appears more similar to adult sleeping state networks (SSN) than awake adult resting state networks. However, even within pediatric FC studies, comparisons regarding age are compounded by developmental differences in state as time spent in different sleep stages changes over the first two years of life. Crucially, individual variability in time spent in each sleep stage poses a challenge for reproducibility and prediction accuracy of extant pediatric, sleeping state fMRI studies such as the Early Life Adversity, Biological Embedding (eLABE) study, Baby Connectome Project (BCP), Developing Human Connectome Project, and the Healthy Brain and Child Development Study. The overarching goals of this Award are to 1) disentangle the relative contributions of sleep stage and age in early brain network development and 2) decode sleep stages in extant infant and toddler sleeping state fMRI. Completion of these goals will enable age and state-specific FC prediction of mental health and clinical outcomes. Towards these goals, infant and toddler sleep stages and FC networks will be characterized using concurrent electroencephalogram (EEG) - fMRI. Aim 1 will optimize pediatric EEG-fMRI acquisition and analysis. Aim 2 will determine pediatric FC SSN development by collecting cross-sectional EEG- fMRI data from 50 children at birth and 24 months of age. Aim 3 will decode sleep stages in out of sample fMRI data (eLABE & BCP). While EEG-fMRI in infants and toddlers is an ambitious and new research direction for the PI, our investigative team has the necessary expertise for success, including FC brain network analysis (PI: Wheelock), pediatric fMRI acquisition and analysis (Smyser), concurrent EEG-fMRI acquisition and analysis (Zempel, Palanca), pediatric EEG sleep staging (Rudock), and machine learning (Lahiri). The knowledge generated from this R01 will be transformative, providing a state-based understanding of early developmental brain networks and a framework for accurate developmental outcome predictions.

NIH Research Projects · FY 2024 · 2024-08

SUMMARY. The Flavivirus and Alphavirus ReVAMPP (FLARE) Center will develop and optimize protein nanoparticle, virion-based, and mRNA vaccine platforms, and monoclonal antibody (mAb)-based treatments to rapidly respond to emerging flaviviruses and alphaviruses with pandemic potential. A key goal is to pair specific antigen designs and vaccine platforms so that successful paradigms can be rapidly adapted in a “plug and play” manner to emerging viruses within the same family. Our suite of antigen design strategies, vaccine platforms, state-of-the-art virological and immunological assays, extensive animal model experience, detailed analysis of correlates of protection, and experienced industry partners (e.g., Moderna) will enable us to generate innovative vaccines and mAb combinations against key targeted prototype flaviviruses and alphaviruses, which then can be applied to related new threats. Moreover, with our collective academic experience in vaccinology and collaborative experience with industry partners, we can make informed Go/No-Go decisions to focus on antigens and vaccines with the greatest chance for clinical efficacy and safety. Our FLARE Center integrates the work of multiple academic groups, with proven records of collaboration, that have the highest levels of expertise in flavivirus and alphavirus biology, antigen design, structural biology, antibody structure and function, mAb generation and characterization, vaccine development, B and T cell immunity, Fc effector functions, and animal challenge studies, all working toward the goal of designing optimized immunogens for incorporation into lipid-encapsulated mRNA, nanoparticles, or other vectors to create vaccines that can protect against infection and disease caused by existing and future flavivirus and alphavirus threats. Our FLARE Center is composed of five primary Research Projects: two vaccine projects that collectively focus on prototype flaviviruses including West Nile (WNV), tick-borne encephalitis (TBEV), and Dengue (DENV) viruses; two vaccine projects, that focus on prototype alphaviruses including chikungunya (CHIKV) and Venezuelan equine encephalitis (VEEV) viruses; and a mAb therapy project that focuses on both flaviviruses (WNV and DENV) and alphaviruses (CHIKV). These Projects are served by an Administrative Core, a Data Management Core, and three Scientific Cores that perform structural biology and protein engineering, animal vaccination and challenge, and correlates of immune protection experiments in collaboration with multiple projects. Our network of expert investigators, innovative Project and Cores, and state-of-the art virological and immunological approaches will enable us to develop vaccine and mAb therapeutics against prototype flaviviruses and alphaviruses that can be readily and rapidly applied to other contemporary and newly emerging related viral threats.

NIH Research Projects · FY 2025 · 2024-08

Pain and substance use disorders (SUD) represent arguably the two most prevalent and costly public health condition in the United States. While vitally important to consider, the intersection of pain and SUD is not just limited to opioid use/abuse. Patients being treated for SUD (opioid and non-opioid) commonly report chronic pain, and, in turn, a history of SUD occurs frequently among patients who receive treatment for chronic pain. Despite the enormous need for new safe and efficacious treatments, the intersection of pain and SUD research remains a surprisingly underexplored area of inquiry, which has resulted in excessive knowledge gaps and limited pain treatment options for people with or in recovery from a SUD. To address this unmet need, we have developed a new postdoctoral training program: the Promoting Excellence through Pain and Addiction Research Enhancement (PREPARE) T90/R90 Training Program. A defining feature of the PREPARE Program will be an emphasis on social determinants of health (SDOH) as they relate to chronic pain and SUD clinical research. SDOH define the conditions in which people are born, grow, live, work, and age, and the inequities in power, money, and resources that are often responsible for disparities in pain and SUD outcomes across the U.S. Our overall goal is to develop outstanding independent investigators capable of sustaining productive clinical and translational research careers addressing the biopsychosocial (emphasis on social) mechanisms underlying chronic pain and SUD development, and/or designing clinical interventions to relieve pain and ameliorate SUD. To facilitate progress toward this goal, the PREPARE Program will complete the following. 1. Recruit and train promising early career investigators (postdoctoral fellows) to conduct mechanistically-based clinical research in pain and SUD. 2. Implement an integrated training program that will equip trainees with new research skills and the knowledge to apply these skills to important and unanswered questions regarding pain and SUD. 3. Create a culture of responsible research conduct and professional excellence to ensure trainees aspire to high standards of scientific integrity and quality. PREPARE will leverage an excellent infrastructure and collaborative network at the Washington University School of Medicine in St. Louis. We anticipate significant success in recruiting and training an outstanding and multidisciplinary group of trainees during the initial funding cycle. Members of the training faculty boast excellent track records of research funding and mentoring experience. Prepare requests support for five postdoctoral trainees (4 T90, 1 R90) from a variety of clinical training backgrounds, each of whom will work with their multidisciplinary mentoring team to create and implement a tailored independent development plan as the blueprint for their training. Trainees will achieve their research and career development objectives through a combination of didactic, research, and professional development activities, and program evaluation will be ongoing and multimodal. The PREPARE Program is committed to promoting excellence among our trainees, and the program will provide a training experience that emphasizes research integrity and ethics.

NIH Research Projects · FY 2025 · 2024-08

Pain and substance use disorders (SUD) represent arguably the two most prevalent and costly public health condition in the United States. While vitally important to consider, the intersection of pain and SUD is not just limited to opioid use/abuse. Patients being treated for SUD (opioid and non-opioid) commonly report chronic pain, and, in turn, a history of SUD occurs frequently among patients who receive treatment for chronic pain. Despite the enormous need for new safe and efficacious treatments, the intersection of pain and SUD research remains a surprisingly underexplored area of inquiry, which has resulted in excessive knowledge gaps and limited pain treatment options for people with or in recovery from a SUD. To address this unmet need, we have developed a new postdoctoral training program: the Promoting Excellence through Pain and Addiction Research Enhancement (PREPARE) T90/R90 Training Program. A defining feature of the PREPARE Program will be an emphasis on social determinants of health (SDOH) as they relate to chronic pain and SUD clinical research. SDOH define the conditions in which people are born, grow, live, work, and age, and the inequities in power, money, and resources that are often responsible for disparities in pain and SUD outcomes across the U.S. Our overall goal is to develop outstanding independent investigators capable of sustaining productive clinical and translational research careers addressing the biopsychosocial (emphasis on social) mechanisms underlying chronic pain and SUD development, and/or designing clinical interventions to relieve pain and ameliorate SUD. To facilitate progress toward this goal, the PREPARE Program will complete the following. 1. Recruit and train promising early career investigators (postdoctoral fellows) to conduct mechanistically-based clinical research in pain and SUD. 2. Implement an integrated training program that will equip trainees with new research skills and the knowledge to apply these skills to important and unanswered questions regarding pain and SUD. 3. Create a culture of responsible research conduct and professional excellence to ensure trainees aspire to high standards of scientific integrity and quality. PREPARE will leverage an excellent infrastructure and collaborative network at the Washington University School of Medicine in St. Louis. We anticipate significant success in recruiting and training an outstanding and multidisciplinary group of trainees during the initial funding cycle. Members of the training faculty boast excellent track records of research funding and mentoring experience. Prepare requests support for five postdoctoral trainees (4 T90, 1 R90) from a variety of clinical training backgrounds, each of whom will work with their multidisciplinary mentoring team to create and implement a tailored independent development plan as the blueprint for their training. Trainees will achieve their research and career development objectives through a combination of didactic, research, and professional development activities, and program evaluation will be ongoing and multimodal. The PREPARE Program is committed to promoting excellence among our trainees, and the program will provide a training experience that emphasizes research integrity and ethics.

NIH Research Projects · FY 2025 · 2024-08

The overall goal of the WashU-ACCERT is to advance cancer control outcomes through community-engaged multi-level research interventions that address the impact of access as defined by affordability (e.g., cost), availability of provider resources, attainability (ability to physically access services), accommodation (does access meet patient needs), and acceptability (patient/provider attitudes) on adverse cancer control outcomes. The specific aims are to: (1) Bring innovation to cancer control community-engaged research through community-academic partnerships in using multi-level research methods and measures to develop transformative solutions; (2) Assemble and engage an exceptional, well-rounded team of cancer health engaged investigators and expand research capabilities among academic and community partners; (3) Organize and integrate Center components in a manner that facilitates innovative approaches for community engagement through multidisciplinary, team science; (4) Develop a research methods, measures and data management shared resource (RMMDM Core) to support the implementation and dissemination of scientifically rigorous internal and cross center projects; (5) Determine opportunities and develop plans to effectively address health access factors (i.e., affordability, availability, attainability, accommodation, and acceptability) and reduce cancer health outcomes for all. WashU-ACCERT builds on a long record of community-engaged research to improve cancer outcomes for all and sustain mechanisms for community input to research. This will be accomplished by engaging investigators from different disciplines and investing in developing community partners and early-stage investigators. We build on expertise in community-engaged research, dissemination science, and the impact of affordability, availability, attainability, accommodation, and acceptability factors to deliver responsive products and use ongoing measures of community engagement to monitor and adjust our processes. By continuously engaging community partners, we will bring meaningful relief through improvements in care, build trust in the research enterprise, and accelerate the improvement of cancer outcomes for all. Our Center will be innovative and have widespread impact by advancing a network of community-engaged cancer researchers, building intellectual capital, and enhancing research capabilities for community engagement in cancer prevention and control. WashU-ACCERT has distinctive features that build on a sustained focus on improving cancer outcomes and apply strategies to build multi-level interventions that are responsive to community needs. These features include a uniquely well-rounded team as part of our Community Responsive Research Program (CRRP), engagement and development of community partners and early-stage investigators, strategic dissemination of products to benefit communities, and a focused strategy for collective integration of projects and cores across ACCERT centers. This Center will ultimately advance cancer control community engagement and promote partnership among community partners.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT Treatment lapses remain one of the most enduring challenges to viral suppression in Africa. These individuals have higher rates of viremia (~70%), morbidity, and mortality, and now represent the majority of those hospitalized with advanced HIV. Even among those who return to care, 30-50% have repeat lapses due to ongoing challenges with care such competing obligations, travel/mobility, clinic-based, or psychosocial barriers. Effective strategies for durably reengaging individuals with treatment lapses must address two steps: they must first be brought back into care, but after return, person-centered strategies are needed to prevent repeat lapses and keep them reengaged long-term. Navigation (NAV) and community-based medication delivery (CB-Med) are strategies that have been found to improve outcomes among those newly initiating or stable on ART, and our preliminary data indicates their complementary mechanisms hold promise to address key challenges at both the return and reengage stages. NAV offers a flexible approach to tailor outreach, care coordination, and psychosocial support to match individuals' unique barriers to care. Leveraging navigators to provide ongoing CB-Med efficiently adds instrumental support to further reduce challenges with medication access. Still, rigorous evidence on the use, timing, and optimal combinations of NAV and CB-Med after treatment lapses is lacking. For example, offering NAV+CB-Med may improve rates of ART re-initiation, but this may not translate to better longer-term outcomes if it is stopped after return and individuals then receive the same care that previously failed. We propose a sequential multiple assignment randomized trial (SMART) among 1270 individuals who are >30 days late for an appointment to assess different sequential combinations of return to care and reengagement strategies. We randomize participants in the first-stage to receive (1) routine phone outreach only (standard of care [SOC]) or (2) NAV+CB-Med for rapid ART re-initiation in the community and reentry support. Among those who return to care, we re-randomize them in the second-stage to: (1) routine care and counseling after return (RCC [SOC]), (2) NAV only after return, or (3) NAV+CB-Med after return. In Aim 1a, we compare phone outreach only vs. NAV+CB-Med on time to ART re-initiation and return to care. In Aim 1b, among individuals who return, we compare RCC, NAV alone, and NAV+CB-Med on retention in care after return (time to missing a pharmacy refill by >14 days). In Aim 2, we assess the overall effectiveness and cost-effectiveness of the six sequential combination return-and-reengage strategies embedded within the SMART design on viral suppression at 18- months after initial randomization (primary outcome). Lastly, in Aim 3 we conduct a mixed-methods evaluation to understand implementation (e.g., reach, adoption, fidelity, acceptability), mechanisms of action, and potential for sustainability among diverse stakeholders (e.g., participants, health care workers, public health officials). This proposal advances a high-priority research agenda to identify the most effective and efficient combination strategies to both return individuals with treatment lapses to care and then keep them reengaged.

NIH Research Projects · FY 2025 · 2024-08

Abstract Androgen receptor (AR) signaling continues to play a dominant role in all stages of prostate cancer (PC), including castration-resistant prostate cancers (CRPCs) that have developed resistance to second generation of AR-antagonists e.g. enzalutamide. We identified a long non-coding RNA (lncRNA), NXTAR (LOC105373241), located convergently to the AR gene that is repressed in human prostate tumors and cell lines, and discovered that its reinstatement promotes binding upstream of the AR promoter, causing significant loss of expression of AR and its splice variant AR-V7. Paradoxically, AR binds to NXTAR promoter, and inhibition of AR by ACK1/TNK2 small molecule inhibitor, (R)-9b, excluded AR from binding to NXTAR promoter. Consequently, histone acetyltransferase GCN5 bound and deposited H3K14 acetylation marks enhancing NXTAR expression. Translational relevance of the negative regulation of AR became apparent when an oligonucleotide derived from NXTAR exon 5 (NXTAR-N5) suppressed AR/AR-V7 expression and prostate cancer cells proliferation. In addition, pharmacological restoration of NXTAR using (R)-9b abrogated enzalutamide-resistant prostate xenograft tumor growth. Overall, our study uncovers a negative feed forward loop, wherein NXTAR acts as a novel prostate tumor-suppressing lncRNA by inhibiting AR/AR-V7 expression, which in turn upregulates NXTAR levels, compromising enzalutamide-resistant prostate cancer. The restoration of NXTAR could be a new therapeutic modality for patients who have acquired resistance to second-generation AR-antagonists. Based on these data we hypothesize that (i) the therapeutic oligonucleotide NXTAR-N5, or (ii) its combination with the ACK1 inhibitor (R)-9b, or (iii) WEE1 inhibitor, AZD-1775 that restores NXTAR levels could be new therapeutic modalities for patients who have acquired resistance to second- generation AR-antagonists. To address this hypothesis, we will pursue the following aims: Aim 1. Determine the mechanism of NXTAR suppression in CRPCs. Aim 2. Synthesis of PSMA targeted `Bivalent and Trivalent’ nanoparticles with NXTAR-N5 oligo, (R)- 9b or/and AZD-1775 inhibitor payloads. Aim 3. In vivo characterization of Bi/Trivalent nanoparticles to overcome Enz-resistance in prostate cancer models, and patient derived xenografts (PDXs).

NIH Research Projects · FY 2025 · 2024-08

Project Summary Chronic kidney diseases, of which glomerular diseases form the most significant component, are quite common and estimated to affect from 5 to 11% of the population. Specific treatment options for various forms of chronic kidney disease in general are extremely limited, in part due to the poor understanding of the pathogenesis of glomerular diseases. What has been apparent since the advent of electron microscopic visualization of the glomerular filtration barrier is that loss of typical podocyte foot process architecture, termed podocyte foot process effacement, is a hallmark of proteinuric glomerular diseases. The overall goal of this research is to better understand the mechanisms that ensure podocyte homeostasis, the maintenance of normal podocyte architecture and adhesion to the glomerular basement membrane, and the pathogenic mechanisms that promote podocyte foot process effacement and the subsequent detachment. By better understanding these mechanisms, targeted therapies to intervene in these pathways can be designed to improve the outcomes of patients either already living with or at risk of glomerular disease. Proof of concept therapeutic approaches are proposed in this project. The overall focus of this application involves several mechanistic aspects of podocyte cytoskeletal dynamics in relation to slit diaphragm stability, foot process shape, and adhesion to the underlying GBM through integrins. Our hypothesis is that podocyte foot process adhesion dynamics can be controlled by modulating tensional homeostasis in cytoskeletal networks of both contractile and non-contractile actin cables that bind integrins and slit diaphragms. The Specific Aims are focused on the functions of synaptopodin (Aim 1), CD2-associated protein (CD2AP; Aim 2), and integrin-based podocyte adhesion in health and disease states (Aim 3). We will investigate how these three aspects of podocyte biology cooperate and interact with each other to ensure podocyte homeostasis under the constant stress of filtration. We will use several novel, innovative approaches to carry out the Aims and will use our mouse models of nephrotic syndrome and Alport syndrome as highly relevant human disease models. The results of the proposed experiments, which also have biochemical, mechanobiological, state of the art imaging, and primary podocyte cell culture components, will lead to an improved understanding of diverse aspects of podocyte biology and reveal clear pathways towards the development of new therapies for patients.

NIH Research Projects · FY 2025 · 2024-08

Monitoring treatment response for Kaposi sarcoma (KS) using current clinical judgement is limited. While objective monitoring of KS lesions is possible, the measurements required are tedious and time-consuming, making them impractical for routine clinical care in busy clinics. This leads clinicians to rely on subjective monitoring strategies, which may prolong treatment and increase chemotherapy exposure. KS remains a major public health concern, persisting as the most common cancer and a leading cause of cancer-related death among men in Malawi, Mozambique, Uganda, and Kenya. Current standard of care methods for monitoring KS treatment response, based on visual assessment and manual measurement, are imprecise and subject to human variation. To address these challenges and advance American leadership in medical innovation, we propose to test a new U.S.-designed technology, SkinScan3D (SS3D), to optimize its performance and integrate into clinical workflows. SS3D combines liquid lens technology and artificial intelligence (AI), providing high-resolution 3D images of KS skin lesions that incorporate lesion height and volume. This portable, low-cost, user-friendly system is designed for use in high-volume clinical settings, supporting both improved patient care and potential technology export. Our specific aims are: Aim 1: Refine SkinScan3D Technology and Usage Protocols for Routine KS Imaging in East Africa. We will work directly with clinicians, nurses, and patients to refine SS3D through focus group discussions, discrete choice experiments to quantify preferences for hardware, software, and standard operating procedures, and iterative design workshops. Aim 2: Compare Reproducibility and Accuracy of KS Lesion Size Measurements Between SS3D and Current Standard of Care Measurement. We will compare the concordance correlation coefficients (reproducibility) and coefficients of determination (accuracy) between SS3D and the manual method. Aim 3: Validate and Optimize SkinScan3D Clinical Workflow in Real-World Settings. We will roll out the refined SS3D package to a variety of practice locations in East Africa and evaluate device usability with the System Usability Scale, acceptability, appropriateness, feasibility, clinic workflows and time burden (time-and-motion studies), and implementation costs (activity-based micro-costing).

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY The broad goal of this proposal is to define a five-year scientific training and career development plan to prepare the candidate to become an independent physician-scientist in the domain of primary immune regulatory disorders (PIRD). The field of primary immune deficiency is rapidly growing, now recognizing around 500 monogenic inborn errors of immunity, of which at least 10% result in immune dysregulation. An increasing number of these disorders are caused by mutations in the JAK-STAT signaling pathway, a signaling cascade that is also a frequent therapeutic target in disorders of the immune system and malignancy. To deliver effective diagnostic, treatment, and management decisions, an in-depth understanding of cell-specific aberrations in these pathways is needed. STAT3 gain-of-function (GOF) syndrome is a PIRD with multi-organ involvement and early onset autoimmunity. We recently demonstrated T cell dysregulation with inherent Th1- skewing and an isolated defect in peripheral Treg cell generation in a model of STAT3 GOF syndrome— findings that challenge current hypotheses regarding disease pathogenesis. The primary scientific goal of this research project is to study the mechanisms contributing to T cell dysregulation in STAT3 GOF syndrome. To achieve this, we will study critical interactions between T and B cells as well as the development, polarization, and function of these cells. Immunophenotyping and transcriptional analysis will be done using a murine model of STAT3 GOF syndrome and viral infection models. In addition, we will establish the impact of STAT3 GOF on antigen-specific responses and mucosal tolerance using a TCR transgenic mouse system and a viral infection model. Furthermore, we plan to utilize a series of in vitro assays to define the impact of STAT3 GOF on T cell polarization in patients. The proposed career development plan incorporates training in technical expertise, grant and scientific writing, responsible conduct of research, as well as mentorship through individualized instruction, didactic courses, University-sponsored seminars, and presentation and attendance at national conferences. Washington University School of Medicine is the ideal training environment given its rich scientific and collaborative culture, and commitment to training physician-scientists. The training will occur under the guidance of the candidate's primary mentor, Dr. Megan Cooper, and the scientific advisory committee, along with a strong group of collaborators. The proposed career development plan and research aims outlined in this application will provide the candidate with the necessary skills and knowledge to become an independent physician-scientist and make significant contributions to the field of primary immune regulatory disorders. Results from these studies have the potential to uncover new biomarkers, targetable cellular pathways, and further insight into disease pathogenesis and human immunology.

NIH Research Projects · FY 2026 · 2024-08

PROJECT ABSTRACT Nearly a third of pregnant patients in the US undergo induction of labor with oxytocin. Despite it being a commonly used medication on Labor & Delivery units around the world, we have a limited understanding of how to dose oxytocin effectively during labor induction as evidenced by its variable therapeutic index and high failure rate of almost 30%. Exposure to high doses of oxytocin for long periods of time is associated with maternal and neonatal morbidity. When there is abnormal labor progression during an induction, the current standard of care is to titrate oxytocin to reach adequate contractions, defined as Montevideo units (MVU) >200 assessed via an intrauterine pressure catheter (IUPC). The theoretic pathway for oxytocin administration is that it increases maternal serum oxytocin, activating the oxytocin receptor (OXTR) and generating adequate contractions. However, we lack mechanistic understanding of how this pathway is affected by oxytocin dosing and our current definition for adequate contractility is flawed as recent data suggest that MVU is an imprecise predictor of induction success. In this proposal, we test the hypothesis that our strategy for assessing contraction adequacy can be improved by using contraction parameters other than MVU, such as peak pressure, duration, frequency, and area under the curve. We will also test the hypothesis that contraction adequacy is associated with maternal serum oxytocin concentration and that myometrial OXTR function is affected by dose and duration of oxytocin. To test these hypotheses, we propose a prospective cohort study of universal IUPC placement in 605 patients undergoing labor induction to develop a prediction model for completion of the first stage of labor using contraction measures and accounting for oxytocin response (Aim 1). We will collect serial maternal serum in a subset of 84 patients from Aim 1 to correlate serum oxytocin concentrations with contraction measures (Aim 2). We will also assess myometrial OXTR function, expression, and localization as it relates to dose and duration of oxytocin exposure (Aim 3). The results of this clinical and translational study will provide mechanistic understanding of how pregnant patients physiologically and functionally respond to exogenous oxytocin so that we may ultimately titrate oxytocin to optimize labor induction success and reduce maternal and fetal morbidity.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Over two-thirds of Americans are overweight or obese, with the recent rise in obesity prevalence strongly correlated with widespread access to palatable, energy-dense foods. These foods, typically highly processed and rich in calories, salt, sugar, and fat, exhibit extraordinary appetitive properties, leading to pathological overeating. For instance, palatable foods can override the body's satiety signals, while regular consumption can cause taste desensitization, making healthier options taste bland in comparison. Furthermore, it is hypothesized that the reinforcing properties of such foods activate reward circuitry, leading to a dissociation between caloric need (the number of calories required to maintain stable weight) and food intake (the number of calories consumed), which ultimately results in obesity. While numerous brain areas are involved in appetite control, this research focuses on the ventral pallidum (VP), a major relay structure in the reward system which plays a key role in processing the pleasure and motivation associated with ingestive behavior. However, the potential to manipulate VP activity to suppress or reverse excessive body weight remains unexplored. In this proposal, I plan to use a multifaceted approach to investigate VP neuronal responses during palatable food consumption and how this activity contributes to pathological consumption behavior. Since foods high in dietary fat disproportionately affect satiety and induce hyperphagia in humans and other animals, I hypothesize that VP neurons are more strongly activated by fat consumption than carbohydrate consumption. To test this, I will record population calcium signals from VP neurons in head-fixed mice consuming mixtures with varying proportions of fats and carbohydrates. With the long-term goal of evaluating whether ventral pallidal manipulations can serve as a viable therapeutic strategy for obesity treatment, I will employ a chronic inactivation strategy on VP neurons and assess its effectiveness in producing weight loss in obese animals. Understanding the neural basis of obesity pathology, and specifically why fat-enriched foods induce hyperphagia, will inform the development of future therapeutics aimed at achieving substantial weight loss in individuals with obesity.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Candidate: Dr. Jennifer Foltz’s doctoral and post-doctoral training has focused on improving natural killer (NK) cell therapy, a type of innate lymphocyte that has shown clinical efficacy in clinical trials of acute myeloid leukemia (AML). Dr. Foltz seeks to integrate her wet-lab and computational training to delineate the mechanisms of resistance to NK cell therapy. Her long-term career goal is to translate these findings into the clinic. Research Career Development Plan: Dr. Foltz is pursuing an independent tenure track investigator position. During this project, she will expand her expertise in genomic research and enhance her skills as a leader and mentor, which is necessary for effectively running a research laboratory. She will attend relevant genomics and epigenomics seminars and journal clubs, participate in early investigator networking groups, leadership courses, grant writing workshops, and present her research at national and international conferences. Research Project: The long-term goal of her proposal is to define novel mechanisms underlying the regulation of NK cell anti-leukemia function and to translate these findings into the clinic through her established collaborations. Recently, NK cell therapies have included NK cells that possess memory—the ability to remember a prior activation, culminating in a more rapid and proficient response upon a secondary challenge. Cytokine-induced memory-like (ML) NK cells are generated through brief IL-12/15/18 activation, followed by differentiation in vitro, or in vivo within AML patients to become ML. Patients treated with ML NK cells have improved clinical outcomes compared to cNK cells; however, not all patients respond. Based upon previous literature and our preliminary data, we hypothesize that ML NK cells exert unique immune pressure on AML driving differential AML resistance mechanisms and unique activation of ML NK versus conventional NK (cNK) cells. This will be interrogated in the following aims: Aim 1: We will elucidate the transcription factors and epigenetic changes underlying cNK versus ML NK cell anti-leukemia functionality. Here we will determine the role of TOX, transcription factor on ML NK cell function, using CRISPR loss-of-function (LoF). We will also define how AML modulates the epigenome of ML and cNK cells with multiomic approaches. Aim 2: We will determine how ML NK cells edit the phenotype of leukemia. Here, we will delineate how AML resistance to ML NK cells is distinct from AML resistant to cNK based upon differential KIR sensitivity and LAG-3 expression using genomic analysis, flow cytometry, and mechanistic LoF in vitro and murine xenograft models. Together, these findings lay the groundwork for Dr. Foltz’s research career on the mechanisms underlying NK cell clinical efficacy.

NSF Awards · FY 2024 · 2024-08

This research project will develop methodologies to address the critical challenges researchers face when merging datasets without unique identifiers. As datasets have become more abundant and diverse, researchers are seeking ways to combine data from multiple sources to tackle important societal questions. A frequent obstacle to linking diverse datasets is the lack of a unique identifier, such as a social security number. This leads to uncertainty in linking records across datasets and computational complexity due to the need for multiple comparisons without prior knowledge of the correspondence between records. This project will develop easy-to-use, computationally efficient, and accurate methods of merging datasets without a unique identifier. Simulations and real-world data will be used to validate the new methods, and open-source software will be developed. The project will provide dedicated training and support for undergraduate and graduate students, including students from underrepresented groups. Overall, the outcomes of this project will advance theoretical understanding, improve research infrastructure, and provide societal benefits by making research findings widely accessible. This research project will address the complex challenge of merging large datasets without unique identifiers by improving probabilistic data integration (record linkage) methods. The central scientific questions involve how to accurately classify record pairs using minimal labeled data and how to enhance computational efficiency when merging large datasets. The approach will involve combining probabilistic modeling with active learning to utilize both labeled and unlabeled data more efficiently. Additionally, it will include the development of new hashing techniques and the use of parallel computing to ensure scalability for datasets containing millions of records. The research will be validated through a comprehensive set of simulation studies and two empirical applications. The newly developed methods will extend beyond their initial application, addressing a wide array of data integration challenges across various scientific disciplines. Open-source software will be distributed, enabling researchers and practitioners to easily incorporate these advanced techniques into their work. The software and accompanying resources will promote broader adoption and utilization of the developed methodologies, enhancing the overall impact and accessibility of the 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.

NIH Research Projects · FY 2024 · 2024-08

SUMMARY Since its inception in 1985, the goals of the Kern Lipid Conference have been to promote metabolic science and increase understanding of metabolic pathobiology and cardiovascular disease. The conference strives to provide an inclusive, open forum for established and young emerging scientists from academia and industry. The 2024 Kern Lipid Conference will be co-chaired by Drs. Jonathan R. Brestoff, Nada A. Abumrad, and Gregory Steinberg and will have the theme “Lipids and Mitochondria in Cardiometabolic Diseases.” It will be held August 12- 14, 2024 at the Viceroy Hotel in Snowmass, Colorado. The primary goals of the 2024 conference are (1) to provide a dynamic interactive environment that leads to novel insights into disease mechanisms involving lipid metabolism and mitochondrial function and (2) to engage and inspire young scientists from diverse backgrounds to develop their careers studying lipid biology, mitochondria metabolism, and cardiometabolic disease pathogenesis. We will examine multiple organ systems including the cardiovascular system, heart, liver, brain, and adipose tissue while delving into metabolic diseases including obesity, diabetes, nonalcoholic fatty liver disease, and atherosclerosis, and other associated conditions such as cancer and neurodegeneration. The program will feature 5 sessions on exciting new areas of research: (1) Lipids and Mitochondrial Metabolism in the Brain, (2) Immune cells and Lipids in Cardiometabolic Diseases, (3) Mitochondria Transfer in Cardiometabolic Diseases, (4) Lipids and Mitochondrial Metabolism in the Regulation of Cardiometabolic Disease Pathogenesis, and (5) Lipids in Cancer. There will be 33 talks over a 3-day period (10 from early career scientists), an evening poster session, and career development sessions for early career scientists. Breaks, lunches, a closing dinner, and a closing reception on the premises promote interactions between participants. Idea exchange is maximized by allocating ample time for questions and discussion after oral presentations. The Kern Conference has traditionally attracted many early career scientists (~40% of the participants) and established scholars in their fields as well as creative scientists from industry. Participation of young scientists is strongly promoted with oral presentation opportunities, the poster session, inviting them to serve as session chairs, and awarding 3 prestigious early-career awards that will advance their career development: the Roger Davis Investigator Award for Transitional Faculty, the David L Williams Lecture and Scholarship Award, and the Franz Simon Poster Award. The setting and meeting format will facilitate interaction and discussion among attendees, making it likely that novel insights into disease mechanisms and therapeutic approaches for cardiometabolic diseases and associated comorbidities will emerge from the 2024 Conference. This R13 application is critical to the success of the 2024 Kern Conference because it will enable us to support the attendance and highlight the research from more early career scientists (graduate students to Assistant Professor), especially those who are from underrepresented groups in biomedical research.

NSF Awards · FY 2024 · 2024-08

This proposal will help to answer one of the most important questions in the geosciences: Why plate tectonics operates on Earth. By considering non-Earth-like compositions the project will also constrain the likelihood of plate tectonics developing on other planets, an important goal in astrophysics. Ultimately, this work will help to place the Earth within the broader context of rocky planets in the galaxy. This project will also provide important educational and research opportunities to graduate students at Penn State University and Washington University in St. Louis. Undergraduate students from astronomy and planetary science will study the development of plate tectonics, giving them interdisciplinary training between astronomy and geoscience that is critical for future leaders studying planets beyond our solar system. Plate tectonics requires the formation of narrow zones of weakened rock that act as plate boundaries, separating stable plate interiors. It is within these plate boundaries that most deformation associated with plate movement occurs. However, the physical mechanism(s) allowing localized weak zones to form are not well understood, nor why this behavior is only seen on Earth. One promising mechanism to explain localized deformation, based on multiple lines of evidence, is deformation-induced reduction of the mineral grain sizes and the activation of grain-size sensitive deformation mechanisms. A planet where the mantle is dominantly composed of one mineral may not be able to experience enough phase mixing during deformation for significant grain size reduction. The goal of this proposal is to test whether certain planet compositions, among those inferred for rocky planets both within our solar system and beyond, would preclude the operation of plate tectonics due to inhibited phase mixing, using a combination of laboratory experiments and theoretical models. Motivated by the potential importance of mineral phase mixing in shear localization, and the compositional variety expected for extra solar planets based on compositions of rock forming elements in stars, this project hypothesizes that planet composition, which dictates the mineral makeup of the mantle, exerts a key control on whether plate tectonics can operate. Specifically, mantles that approach 50-50 mixtures of the two dominant mineral phases may be most favorable for plate tectonics, while plate tectonics may be precluded for planets whose mantles are near monominerallic. This hypothesis will be tested with a project integrating new rock deformation experiments with new numerical models of mantle convection to determine which mantle compositions are most favorable for plate tectonics and which, if any, preclude plate tectonics. Experiments will deform relevant materials to high strains to assess the factors that control the rates of phase mixing. Specifically, these experiments will 1) determine how the relative proportions and strength contrast between the dominant mineral phases of mantle rock affects the efficiency of phase mixing and grain size reduction. Numerical models of phase mixing, benchmarked against these experiments, will be used to develop parameterizations of this process to include in mantle convection models. The mantle convection models will then be used to 2) determine how the conditions needed for plate tectonics to develop are modified when the physics of phase mixing is considered; and 3) determine how the volume fractions of, and strength contrast between, primary and secondary mineral phases, affects the conditions for plate tectonics. Finally, the modeling and experimental work will be integrated to 4) assess the likelihood of plate tectonics across the range of proposed mantle compositions for exoplanets. This work will provide new insight into the mineralogical factors that control whether plate tectonics can develop on rocky planets, helping to both explain its operation on Earth and give new constraints on its feasibility on exoplanets. In addition, this project will provide the most complete description of mineral phase mixing, and its dependence on rock composition, to date and be the first to incorporate the physics of mineral phase mixing into mantle convection models of plate tectonics on Earth and other planets. 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 2024 · 2024-08

PROJECT SUMMARY / ABSTRACT Uropathogenic Escherichia coli (UPEC), the major causative agent of urinary tract infections, can colonize the bladder (cystitis) and ascend the ureter leading to infection within the kidney (pyelonephritis). Though less frequent than cystitis, pyelonephritis carries increased health risks, including hypertension, renal abscess formation, and renal scarring. Nevertheless, the mechanisms of UPEC pathogenesis during pyelonephritis have remained elusive due to lack of an optimal preclinical infection model. Published work from our group has established that males exhibit an elevated susceptibility to chronic pyelonephritis and renal abscess formation. This inherent sex bias in UTI outcomes is androgen dependent, leading us to create new published models of ascending UTI in androgen-exposed female mice that enable investigation of UPEC virulence strategies within the kidney. The UPEC secreted toxin alpha-hemolysin (HlyA) elicits cell lysis and ATP release from various mammalian cell types in vitro, but was previously shown to be dispensable during UPEC cystitis. Preliminary studies using our updated mouse model of ascending UTI demonstrated that HlyA is required for optimal UPEC colonization and associated with severe pathology and renal abscess formation in androgen-exposed hosts. This initial work is congruent with epidemiologic data showing that ~80% of clinical UPEC isolated from patients with pyelonephritis are HlyA positive, versus only 40% of cystitis isolates. Purinoreceptors (P2X) are host cell membrane channels that open upon sensing extracellular ATP and facilitate non-selective passage of small cations. Interestingly, the P2X4 isotype expressed ubiquitously throughout the renal tubular epithelium, is allosterically activated by direct interactions with testosterone; modulation of P2X4 function by testosterone increases receptor affinity for ATP, driving increased ion permeability and subsequent pore conductance. We have found that P2X receptors amplify HlyA cytotoxicity in vitro. Specifically, exogenous testosterone significantly enhances HlyA-mediated lysis of renal epithelial cells, and this effect is abolished in the presence of a non-selective P2X inhibitor. Leveraging updated models of ascending UTI, small-molecule P2X inhibitors, and our in vitro model of renal collecting duct infection, we will test the central hypothesis that UPEC alpha-hemolysin drives renal pathology during pyelonephritis, and its activity is augmented by testosterone via enhancement of P2X channel function. Completion of this work will delineate the contribution of HlyA to UPEC pathogenesis within the kidney, determine the mechanism which facilitates the sex-biased pathogenic effect of HlyA, and define the contribution of pharmacologically targetable host P2X4 channels to HlyA toxicity during pyelonephritis.