Washington University

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Tobacco use treatment remains limited as only 1 in 5 patients who would benefit receive a prescription from their doctor, only 1 in 3 patients who receive a prescription use the medication, and only 1 in 3 patients who use the medication successfully quit smoking. These gaps require solutions on multiple fronts: precision medicine to improve the personal efficacy of the treatments, and implementation science to ensure that personalized approaches are leading to evidence-based tobacco use treatment being prescribed and used. Still, it remains unknown whether personalized approaches, particularly those that use genetics and other biological markers to inform specific patient risks and recommend specific treatments, are accelerating progress toward more widespread use of effective treatment. This K02 proposes to address two important yet understudied areas, implementation speed and scale-up, to understand how we can bring, with less delay, personalized guidance for tobacco use treatment to more people who would benefit. I am a recently tenured investigator making important contributions in bringing genetics-informed behavioral interventions into real- world settings to improve uptake and engagement with tobacco use treatment. Through my two active NIH R01 trials (R01 CA268030 and R01 DA056050), there are data available to address a novel question: “How fast and how far can innovations in personalized tobacco use treatment spread to improve population health?” While important, the areas of focus on speed and scale-up are not in scope with these R01s. Instead, this K02 proposal is uniquely situated to advance my scientific leadership in these areas of high priority for the fields of substance use and implementation science. In pursuit of this goal, I will lead the following integrated Research and Career Development aims: (1) investigate factors influencing the speed of implementation of personalized tobacco use treatment; (2) determine the potential for implementation scale-up of personalized tobacco use treatment; and (3) maximize growth in mentorship of early-stage investigators to become the next generation of scientists focused on implementation of tobacco and substance use prevention and treatment interventions. I will collaborate closely with a purposefully selected group of investigators at Washington University and external experts who will contribute to my learning in genomic discovery, behavioral intervention development, precision medicine in the clinic and community, electronic health record integration, and implementation science. These collaborations will help me gain new content and methodological skills, including abilities to synthesize datasets across multiple trials and collaborative projects. In summary, this Independent Scientist Award is essential to advancing my career development and trajectory so that I can have greater impact on the field and its understanding of how to speed and scale-up personalized tobacco use treatment to more individuals who could benefit.

NIH Research Projects · FY 2026 · 2026-05

SUMMARY For successful fertilization in vivo, mammalian sperm must first undergo capacitation, a maturation step that enables hyperactive motility and acrosomal exocytosis. Hyperactive motility is triggered by calcium influx through the sperm-specific calcium channel CatSper, but premature CatSper activation can lead to calcium overload, channel degradation, and loss of fertilizing capacity. To prevent this, CatSper must remain inactive until sperm reach the oviduct. Prevention of premature CatSper activation in the male reproductive tract has long been attributed to acidic epididymal pH, which inhibits CatSper. However, the factors that prevent CatSper activation before sperm reach epididymis and after they leave it remain unknown. Based on our recently published study in a murine model, this project will test the central hypothesis that human CatSper activation is regulated within the male and female reproductive tracts by four key factors: pH, temperature, polyamines, and progesterone. In this model, the low temperature of the testis and the acidic pH of the epididymis maintain CatSper in a closed state. When sperm mix with seminal plasma, they encounter polyamines, which further inhibit CatSper activity, even as the sperm travel through the warm and slightly alkaline environment of the cervix and oviduct. During sperm capacitation in the oviduct, and after prolonged exposure to oviductal fluids, polyamines dissociate from sperm. At this stage, CatSper is activated by high temperature, alkaline pH, and factors released by the ovulated egg, such as progesterone. This hypothesis will be tested in three specific aims. Aim 1 is to define the mechanism by which CatSper is regulated by temperature in human sperm. This aim will test the hypothesis that temperature alters human CatSper activity by influencing its voltage gating, pH- and progesterone- sensitivity. Aim 2 is to determine the effect of these four factors on CatSper impact on sperm motility and intracellular calcium concentrations in both murine and human sperm. These two aims test the hypothesis that the seminal plasma components inactivate CatSper and greatly reduce its temperature sensitivity, thereby protecting CatSper from activation until sperm reach the oviduct. Aim 3 is to determine the molecular mechanisms underlying infertility in patients with varicocele. This aim will test the hypothesis that, in patients with varicocele, high testicular temperature, lack of acidic pH, and absence of protective polyamines mimic conditions that sperm normally only encounter in the oviduct. Thus, sperm CatSper is prematurely activated in the testis, leading to calcium overload and shortened sperm life span. Completion of these aims will rely on the unique abilities of the investigators’ laboratories to conduct electrophysiological measurements, motility analysis, and calcium imaging in mouse and human sperm. The proposed work will reveal key physiological regulators of CatSper, and may reveal the molecular mechanism underlying infertility in patients with varicocele.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT The therapeutic benefits of allogeneic hematopoietic cell transplantation (allo-HCT) are primarily derived from a graft-versus-leukemia (GvL) effect that is mediated by T cells which also cause graft-versus-host disease (GvHD). The disparate effects of GvHD and GvL are difficult to separate, and strategies directed against GvHD often adversely affect survival by reducing the beneficial GvL effect. As a result, overall mortality rates from leukemia relapse after allo-HCT have actually increased over the past 40 years. Thus, GvHD and leukemia relapse are the two most significant barriers to the success of allo-HCT. Therefore, finding a means to prevent both GvHD and leukemia relapse is a significant unmet need and major clinical goal. Although several groups, including ours, have proposed therapeutic strategies to reduce GvHD without abrogating GvL in animal models and human patients, no one has clearly identified the optimal therapeutic targets to selectively inhibit GvHD over GvL. More importantly, the mechanisms by which allogeneic donor T cells differentially modulate GvHD and GvL remain unknown. This gap in our mechanistic understanding hinders our ability to separate GvHD from GvL. Accordingly, using an unbiased genome-wide CRISPR/Cas9 guide RNA library screen and gene set enrichment analysis (GSEA), we have identified and prioritized very-low-density lipoprotein receptor (VLDLR) as a novel therapeutic target to separate GvHD from GvL. Our animal studies with VLDLR knock-out (KO) T cells suggest that targeting VLDLR is a promising approach to prevent both GvHD and leukemia relapse. Thus, we hypothesize that pharmacologic inhibition of VLDLR may separate GvHD from GvL. We will test this hypothesis in Specific Aim 1, using two distinct and independent mouse models of allo-HCT. We will also define the cellular mechanisms underlying the separation of GvHD from GvL by genetic/pharmacologic blockade of VLDLR. In Specific Aim 2, we will elucidate the molecular mechanisms by which VLDLR blockade selectively reduces GvHD over GvL. We have made three critical observations relating to T cells from VLDLR KO mice compared to those from wild-type (WT) mice: 1) increased frequencies of regulatory T cells, 2) reduced CD4 T cell proliferation when stimulated with allogeneic antigen presenting cells (APCs), but not with leukemic cells, and 3) normal CD8 T cell responses against both allogeneic APCs and leukemic cells. These findings may explain why VLDLR KO T cells selectively reduce GvHD over GvL. Our RNA-seq and GSEA studies of VLDLR KO vs. WT T cells stimulated with allogeneic APCs have identified Klrc1 as a top candidate, which encodes immune modulatory NKG2A. Of note, Klrc1 is upregulated only in VLDLR KO CD4 T cells, not CD8. Thus, we hypothesize that blocking VLDLR prevents GvHD and leukemia relapse by upregulating Klrc1 in CD4 T cells. Our innovative findings can potentially be practice-changing, resulting in a first-in-human clinical trial targeting VLDLR to modulate GvHD/GvL since the amino acid sequence identity between murine and human VLDLR is 97%. Thus, our studies have a substantial impact on the fields of allo-HCT and transplant immunology.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract Nine NIH-funded investigators with similar but independent super-resolution microscopy needs are requesting funding to acquire an Abberior Mirava 3D STED microscope to enable imaging of molecular topographies in fixed or live tissues and cells at unprecedented resolution at the scale of tens of nanometers with fluorescent probes. This platform will be maintained in the Washington University Center for Cellular Imaging (WUCCI), an institution-wide shared technology resource. There is no instrument like this at WUCCI or anywhere else on campus. One huge advantage of this system is that it works just like a confocal microscope in terms of the field of view, imaging depth, and data acquisition interface. As such, many investigators will be ready to utilize it immediately. Sample preparation is nearly identical to conventional confocal microscopy, except for the use of specific fluorescent probes, and care taken to use mounting or immersion media and cover slips with matching refractive indexes to enable maximum resolution. STED technology breaks the traditional barrier of optical microscopy set by the diffraction-limited point spread function (PSF) by PSF engineering, achieving 40 nm resolution, exceeding the resolution of the already heavily subscribed Nikon NSPARC and Zeiss Airyscan. The major user group comprises nine investigators from 6 departments who will utilize this microscope to enable a wide range of basic and translational research studies. Scientific goals include understanding primary cilia, the role of actin cytoskeleton dynamics in intracellular networks, energy and lipid storage and lipid droplet or to resupply membranes with lipids, mechanobiological mechanisms underlying kidney glomerular filtration, glutamate receptor geography at cochlear synapses, receptor dynamics in pancreatic islet hormone secretion and neuroinflammation biomarkers for biological imaging and chemotherapeutics. Given its location in a busy core facility, we expect this microscope to be impactful to many research programs beyond the initial major user groups. The expertise and institutional support for this instrument are excellent. Dr. Mark Rutherford, Associate Professor of Otolaryngology, used STED microscopy extensively during the historical development of this technology. Dr. Rosa-Molinar and the WUCCI staff have a long-standing track record of training NIH- funded researchers to optimize their use of state-of-the-art microscopy methods. In support of this S10 grant application, the Washington University School of Medicine will commit $176,647 of matching funds for the acquisition of the instrumentation plus an additional $125,000 operational support ($25,000 per year for five years) to ensure the long-term success of this equipment.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Background: Neoantigen cancer vaccines have shown promising clinical potential in preventing or delaying tumor recurrence in a fraction of people. The low efficacy of neoantigen cancer vaccines can be attributed to several reasons, including the low abundance of antigen-specific CD8 T cell responses induced by these therapies. Additionally, accumulating evidence suggests that suppressive cells such as Foxp3+ Tregs or Foxp3-negative type 1 regulatory CD4 T cells (Tr1) are profoundly immunosuppressive and function as a major obstacle to cancer vaccine-induced antitumor responses. Our recent publication in Nature demonstrated that the antitumor efficacy of neoantigen cancer vaccines depends on the peptide dose of MHC-II–restricted neoantigens included in the vaccine formulation. Whereas vaccines comprised of MHC-I restricted neoantigens plus low doses of MHC-II-restricted neoantigens (LDVax) promote tumor rejection, similar vaccines containing high doses of the same MHC-II neoantigen (HDVax) induce Tr1 cells and inhibit rejection. Notably, CD4 T cells with a Tr1-like signature have been detected in cancer patients and correlate with poor patients’ outcome. Objective/Hypothesis: Our preliminary studies indicate that neoantigen cancer vaccines containing high doses of altered peptide ligands (APLs) with low MHC-II binding affinity do not induce Tr1 cells and instead promote tumor rejection. Additionally, Tr1 induction also required antigen presentation by type 2 dendritic cells (cDC2) and the participation of signaling by EBI3 subunit of the inhibitory cytokine IL-35. Based on these findings, we hypothesize that DC2/monocyte-derived IL-35 synergize with strong interactions between peptide and MHC-II molecules and T cell receptors (pMHC: TCR) to drive Tr1 cell induction and thereby inhibit the antitumor efficacy of neoantigen cancer vaccines. Specific Aims: (1) Elucidate the role of the EBI3 cytokine subunit chain of IL-35 in the induction of Tr1 cells; and (2) Define the factors that regulate expression of IL-35 signaling receptors (IL-12Rβ2 and IL-27Rα) required for Tr1 cell induction. Study design: Using our well characterized tumor models, we will identify the cellular sources of IL-35 using IL-35 reporter mice and assess how IL-35 blockade alters the phenotype and effector function of Tr1 and CD8 T cells. We will test whether IL-35 neutralization enhances vaccine-driven tumor rejection by diminishing Tr1-mediated suppression and boosting CD8 T cell cytotoxicity. We anticipate that IL-35 blockade will reduce Tr1 differentiation, reprogram CD4 T cells toward a Th1 phenotype, and enhance CD8 T cell effector responses. In Aim 2, we will determine whether strong pMHC: TCR interaction favors the differentiation of tumor-specific CD4 T cells into Tr1 cells by upregulating IL-12Rβ2 and IL-27Rα receptors involved in the signaling of IL-35. We expect that stronger interaction in CD4 T cells correlates with Tr1 differentiation and suppression of antitumor immunity.

NIH Research Projects · FY 2026 · 2026-05

Solid tumors may evade immune destruction due to T-cell or dendritic cell (DC) dysfunction, and current immunotherapies face limitations in solid tumors. This project addresses these challenges by leveraging our myeloid chimeric antigen receptor (CAR) expertise to mechanistically characterize a novel DC-based immunotherapy: αB7H3-TLR4 CAR-DCs. These engineered DCs express a B7H3-specific CAR fused to the intracellular signaling domain of Toll-like receptor 4 (TLR4). Preliminary data demonstrate that αB7H3-TLR4 CAR-DCs efficiently capture tumor antigens from tumor cells expressing the tumor associated antigen B7H3, potently upregulate costimulatory molecules, and robustly cross-prime naïve tumor-specific CD8⁺ T cells, leading to complete tumor rejection and durable immune memory in a heterogenous B7H3-expressing sarcoma model. This project will dissect the distinct roles of MyD88 and TRIF signaling pathways downstream of TLR4 in these CAR-DCs. Aim 1 will define the role of MyD88 in acute T-cell priming and effector differentiation, while Aim 2 will define the role of TRIF in long-term memory and recall responses. By elucidating these mechanisms, we will provide a roadmap for rationally designing DC-based therapies that maximize both immediate tumor control and durable immune protection, ultimately leading to more effective treatments for a wide range of solid tumors.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY: Prostate cancer is the most common non-cutaneous malignancy diagnosed in men. Disseminated disease is incurable and metastatic castrate resistant prostate cancer (mCRPC) is a leading cause of cancer death. Systemically administered radiopharmaceuticals can localize ionizing radiation to all sites of metastatic disease and have recently been approved for mCRPC. However, only modest progression free and overall survival benefits have been realized. Quantitative imaging of the radiotherapy distribution can be used to guide optimal use and to maximize therapeutic index. This theranostic approach, when used with high linear energy transfer emissions produce irreparable DNA damage, can guide precision treatment. Meitner-Auger electron (MAe-) emitters deposit high absorbed doses in circumscribed fields at the sub-micron scale. This spares distant normal tissue, but requires that decay occurs directly upon critical cancer cell structures. Chelator dependent radiometal agents typically cannot access the nucleus, and labile halogens are avoided because of instability. Here, we investigate the first-in-man clinical imaging of a stable bromine-77 ligand that targets an abundant genome-associate target: PARP1. The drug, [77Br]Br-WC-DZ, has subnanomal affinity for PARP1 and is produced in 15 min using a single-step with high yield and purity. Through novel observations, we reveal for the first time that bromine-77 can be used with clinical positron emission tomography systems for high resolution, high sensitivity and quantitative imaging. Together, the high linear energy profile and quantitative imaging features of this DNA-targeted theranostic result in significant anticancer therapeutic potential. We propose translation and evaluation of [77Br]Br-WC-DZ in men with mCRPC to assess feasibility, distribution and imaging characteristics. Simulations and experimental phantom acquisitions are used to optimize image quality and clinical protocol, in Specific Aim 1. In Aim 2, we perform eIND enabling studies of tolerability and absorbed dose. In Aim 3, we initiate an Early Phase I study to assess the safety and distribution of this longer- lived [77Br]Br-WC-DZ (56 h), and then evaluate the complementary information from a PARP1 targeted agent with conventional F-18 (0.9 h; [18F]-FTT). This trial provides input data for further precision image-guided therapeutic intervention of this potent therapy. We leverage the expertise and experience of the team along with institutional strengths in PET tracer development, translation and analysis. This group of investigators and the strength of our data addresses key issues in prostate cancer radiopharmaceutical deployment and demonstrate the potential to realize the transformative capabilities of molecularly targeted radiotherapy for men suffering from mCRPC.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY The US and world populations face numerous reproductive challenges. For example, an estimated 13% of women in their reproductive years have impaired fecundity. Furthermore, the World Health Organization estimates that 15% of all pregnant women — 14 million per year — will experience an obstetric complication such as preterm birth, preeclampsia, or postpartum hemorrhage. Between 10% and 20% of reproductive-age women have endometriosis, which impairs fertility. Additionally, 7% of men globally are affected by infertility. Finally, infertility is a potential biomarker of both present and future health. To solve these and other reproductive challenges, we must rigorously define the etiologies and develop new therapies and technologies to prevent or treat them. To advance science in this area, this R13 proposal requests funds to support an international symposium entitled “Membrane Excitability and Reproductive Biology.” This will be the 79th Annual Symposium of the Society of General Physiologists (SGP) and will be held September 2 through 6, 2026, at the Marine Biological Laboratory in Woods Hole, MA. The SGP symposia have a reputation as leading meetings for physiologists and biophysicists spanning all career stages and professional levels, across several disciplines. Each year the meeting topic is unique, designed to highlight emerging and important research areas within the field of physiology. The 2026 meeting will bring together ~150 scientists and trainees to discuss cutting-edge fundamental and applied research relating to the role of membrane excitability in reproduction and novel technologies for studying these problems. The overarching goals of the meeting are to inspire and recognize young investigators, create a place for scientific exchange, and disseminate new and significant discoveries that push forward our fundamental understanding of reproduction. We will achieve these goals by pursuing the following three Specific Aims: 1) Provide an opportunity for experts in the field to present cutting-edge science on the role of membrane proteins in reproduction. 2) Promote early-career investigators within the field of reproduction, and 3) Foster new, interdisciplinary collaborations. By providing an interactive forum to discuss interdisciplinary and cutting-edge reproductive research, the 79th SGP meeting will stimulate new ideas and technologies to advance the field of reproduction.

NIH Research Projects · FY 2026 · 2026-05

Modified Project Summary/Abstract Section More than 50% of people receiving HIV pre-exposure prophylaxis (PrEP) discontinue PrEP within 6 -12 months of initiation partly due to social and structural barriers, resulting in an unacceptable rate of new infections disproportionately affecting communities with less access to PrEP. While some may appropriately discontinue based on lifestyle changes, HIV seroconversion among those who discontinue is high, indicating premature discontinuation or lack of timely re-engagement in PrEP care. Despite identified barriers to PrEP persistence (encompassing retention and adherence), effective implementation strategies to support persistence are lacking compared to other steps of the HIV prevention continuum such as linkage and uptake. A greater understanding of patient preferences about PrEP persistence and re-engagement, with a focus on the factors most relevant to urban vs. rural clinics, is critical to creating innovative strategies to end the HIV epidemic. This research applies multidisciplinary methods to design and pilot-test preference-informed implementation strategies to improve PrEP persistence in urban and rural settings in Missouri, an Ending the HIV Epidemic priority state due to the burden of both urban and rural epidemics. This career development award will provide Dr. Aditi Ramakrishnan with the mentored training and research expertise to launch her career as an independent clinician-investigator leading the 1) design of preference-informed and community-engaged implementation strategies and 2) rigorous testing through implementation trials in urban and rural contexts. To achieve this goal, Dr. Ramakrishnan has assembled an expert mentoring team and proposed an impactful training plan to develop her skills in 1) stated preference methods for implementation science, 2) human-centered design and community-engaged research methods, and 3) implementation trial design. These training objectives complement a research study with the following Specific Aims: 1) Identify patient and provider preferences for HIV prevention strategies supporting persistence and re-engagement through a discrete choice experiment, 2) Design a multicomponent strategy, PREFER-PrEP, to improve persistence and re-engagement among individuals with ongoing indications for PrEP using human-centered design principles, and 3) Assess implementation outcomes (e.g., acceptability) and persistence (e.g., retention, adherence) of the PREFER-PrEP prototype. This study will leverage robust community-academic partnerships across urban and rural Missouri and provide preliminary data for an R01 application to test the PREFER-PrEP strategy through a Type 3 hybrid effectiveness-implementation cluster randomized controlled trial to optimize HIV prevention services. This career development award training, mentorship, and research, within the rich environment of Washington University in St. Louis School of Medicine, will position Dr. Ramakrishnan to independently lead the design and testing of preference-informed, community-engaged implementation strategies and interventions to improve HIV prevention in priority regions.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT: This S10 Shared Instrumentation Grant application from Washington University (WashU) in St. Louis requests funds in partial support of the purchase of a Sybmia Pro.specta X3 scanner (Siemens Medical Solutions USA). This hybrid single photon emission computed tomography and x-ray computed tomography (SPECT/CT) system will be housed in a dedicated Nuclear Medicine research facility for the non-invasive assessment of therapeutic and diagnostic (theranostic) radiopharmaceuticals. This state-of-the-art instrument will be a critical, broadly used resource for the clinical and translational neuroscience, cardiovascular and oncology research programmes at WashU. The requested SPECT/CT will be the only research dedicated SPECT/CT system across the WashU clinical enterprise. At present, WashU through its affiliated Hospitals, has access to 7 SPECT/CT scanners across the medical campus. These are dedicated for standard of care and clinical trial workflows, 1 of them being at the Children’s hospital (out-of-reach for research), and 2 of the SPECT scanners are obsolete and only used for planar imaging. These systems are all >10 yr, and they are heavily utilized, at nearly 8 h of scan time per day average (utilization >85%), which does not include protocol development and maintenance. Access for research is highly restricted and there is no support for the special attention required for clinical research. Additionally, in the greater St. Louis region beyond WashU there is no research SPECT/CT hardware, and the nearest research SPECT/CT scanners are located at University of Missouri Veterinary Health Center (2.5 h drive), dedicated for non-human use. The Symbia Pro.specta incorporates advanced workflows including advanced iterative data driven motion correction features are critical for advanced quantitative imaging-; a redesigned quantitative framework for therapeutic absorbed dose assessment; and best-in-the-field collimators. The requested SPECT/CT scanner will anchor major new research efforts in theranostics for cancer, cardiovascular disease and neuroscience at WashU. Towards this end, Pamela Woodard, Radiology Chair and MIR Director, and Timothy Eberlein, Director, Alvin J. Siteman Cancer Center, have made substantial financial and administrative commitments to ensure the successful utilization of this instrument. These include funds for (1) installation and renovation costs, (2) adjacent radioactive handling and patient-administration space, (3) maintenance for the instrument, (4) pilot funds for protocol development and (5) personnel support. A new Section of Medical Physics is being established to harness the outstanding imaging science and translational radiopharmaceutical expertise at WashU that will be co-located with this centerpiece scanner. The combination of advanced instrumentation and robust support from our institution will enable groundbreaking discoveries and innovations that will benefit both our research community and patients, reflecting our dedication to excellence in scientific inquiry and healthcare.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT Bone marrow adipose tissue (BMAT) is a heterogenous and understudied adipose depot that fills approximately 70% of the adult human skeleton. Despite its abundance, the regulatory mechanisms and functional roles of bone marrow adipocytes (BMAds) remain poorly understood, particularly in the context of constitutive BMAd catabolism and its implications for skeletal health. The overall goal of this project is to define the neuro-adipose-bone crosstalk within the cBMAd-containing skeletal niche to promote the design and implementation of novel strategies to support bone health. Our central hypothesis is that activation of adaptive cBMAd lipolysis drives transcriptional remodeling to support anabolic cBMAd-osteoblast coupling in states of high sympathetic tone and neurosystemic stress, providing localized protection against age- and disease- associated bone loss. To test this hypothesis, we propose two specific aims. Aim 1 will define the mechanisms of cBMAd-mediated anabolism and bone protection and explore conservation in aged/post-menopausal states while creating new bioinformatic-based digital twin models that will inform personalized strategies to preserve skeletal integrity by computationally modeling cBMAd responses to physiological and pathological stress. Aim 2 will isolate the fate of catabolized cBMAds, quantify the changes in bone and muscle that occur after complete cBMAd loss while clarifying potential for recovery, and determine the lifespan and differentiation potential of cBMAds in vivo. This moves beyond established pathways to define mechanisms underlying the local role of cBMAds in the mitigation of the bone suppressive effects of high sympathetic tone. In addition to informing therapies to support healthy skeletal aging, this research has important implications for prevention of bone loss and fracture in diverse forms of wasting and cachexia and will support the development of new treatments to increase and preserve bone mass in settings of neurosystemic stress.

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract Cardiac fibrosis compromises left ventricular (LV) function and worsens clinical outcomes in heart failure (HF). Currently, there are no clinical therapies that target fibrosis in the failing heart. Platelet-derived growth factor (PDGF), a central mediator of fibrotic responses, acts via two receptors - PDGFRα and PDGFRβ. Our pilot studies using explant cultures, flow sorting, single cell RNA sequencing (scRNAseq), and in vivo mouse models have uncovered a novel stem cell antigen(Sca)-1-expressing PDGFRα+ multipotent cardiac fibroblast population that sources myofibroblasts, interacts with tissue macrophages, and drives fibrotic and inflammatory responses during adverse LV remodeling. During HF, these cells decrease PDGFRα expression and instead upregulate PDGFRβ. The role of PDGFRβ in cardiac fibroblast biology in HF is unknown. We propose the novel hypothesis that a heretofore unrecognized Sca-1+PDGFRβ expressing cardiac fibroblast with mesenchymal stem cell features (termed cFMSCs) are key drivers of a PDGFRβ-dependent immunofibrotic axis in HF. Three Aims will test this hypothesis. In Aim 1, using a murine coronary ligation model, in vitro studies of cell function, scRNAseq, and inducible cardiac fibroblast-specific and Sca1+ cell-specific PDGFRβ-deletion mouse models, we will comprehensively define the importance of PDGFRβ in cFMSC cell function in ischemic HF. We will isolate Sca1+PDGFRα+ cFMSCs and assess PDGFR β-dependent myofibroblast differentiation, multipotency, downstream signaling and immuno-fibrotic secretome, and cFMSC-macrophage interactions. scRNAseq of sorted cells will assess cFMSC subpopulations and changes in transcriptomic profiles. In Aim 2, we will establish the pathogenetic role of cFMSC-localized PDGFRβ in chronic HF, by using inducible cardiac fibroblast-specific PDGFRβ knockout mice, deleting cFMSC PDGFRβ during chronic HF, and assessing late effects on LV remodeling, fibrosis, tissue macrophages, and inflammatory profiles. To establish necessity of cFMSC PDGFRβ signaling, cardiac fibroblast PDGFRβ loss will be induced by tamoxifen in PDGFRβf/f-Tcf21MerCreMer mice 4 w post- MI and LV remodeling, fibrosis, and tissue macrophage and inflammatory profiles will be assessed 6 w Iater. The effects of sustained cardiac fibroblast PDGFRβ activation on LV remodeling will be assessed using PDGFRβ[S]D849V-Tcf21MerCreMer mice. To establish sufficiency of cFMSC PDGFRβ signaling, we will perform intramyocardial adoptive transfer of sorted PDGFRβ-deficient and -competent Sca1+PDGFRα+ cFMSCs from HF mice into naïve mice and assess late LV remodeling and fibrosis. In Aim 3, we will test potentially translatable therapies to antagonize cFMSC PDGFRβ signaling in chronic HF, including CP-67345, a specific small molecule PDGFRβ inhibitor, fibroblast-targeted nanoparticle delivery of PDGFRβ siRNA, and anti-PDGFRβ neutralizing antibody. We will measure the effects of these therapies on LV remodeling, fibrosis, cFMSC abundance, cardiac macrophages, and tissue inflammation. By conclusively defining the role of cFMSCs and fibroblast PDGFRβ in pathological LV remodeling, these studies will provide novel perspectives on the immunofibrotic response in HF.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY The 2026 biennial meeting of the Orthopaedic Research Society-International Section for Fracture Repair is entitled: ORS-ISFR 19th Biennial Meeting: Advancing Bone Repair – From Basic Science to Clinical Solutions. The overall objective of this two-day meeting is to promote state-of-the-art research and scientific discourse on topics related to bone repair, with an emphasis on the ongoing need for collaboration between basic scientists, engineers and clinicians. We are committed to an interactive conference that is welcoming for trainees and early-stage investigators, with opportunities to present research, moderate sessions and network. The meeting program has been designed based on the success of past meetings, but with changes based on attendee feedback from the prior meeting. The meeting will address the most challenging problems in bone repair, with a focus on recent advances. Each session will address topics of relevance to the research priorities of the NIH. Three sessions on Day 1 will focus on basic and translational science: a) Advanced model systems and -omics in bone healing; b) Microenvironmental cues and cell metabolism in bone regeneration; and c) Innervation and angiogenesis in bone repair. Day 2 will have three clinically relevant sessions: a) Early detection of failed healing; b) Immune system and fracture – from infection to healing; c) The immune-bone axis in polytrauma and healing. There is often an information gap between what front-line clinicians treating fractures recognize as important problems, and problems that basic scientists perceive as most important. This ISFR conference aims to bridge this gap and accomplish three objectives: 1) provide a forum for clinicians to learn about the latest in basic and translational research, 2) expose basic scientists to the clinical issues that are most pressing in orthopaedic trauma, and 3) foster collaborations between researchers and clinician-scientists. Multidisciplinary approaches are essential to address challenging clinical problems. The ORS-ISFR 19th Biennial Meeting will advance understanding of fracture healing across basic, translational, and clinical perspectives.

NIH Research Projects · FY 2026 · 2026-05

Project Summary The overall goal of this project is to evaluate the long-term impact of in utero oxycodone exposure, opioid maintenance therapy and opioid-withdrawal mitigation strategies on neuro-behavioral development, brain structure and volume and reward processing. Clinical studies have shown concerning long-term, neurodevelopmental outcomes associated with in utero opioid exposure, which include lower social competence scores, memory deficits, and increased risk for behavioral problems and hyperactivity disorders. Clinical data is limited due to a number of challenges, including quality of maternal-infant bonding and care, maternal poly- substance use, epigenetic influences, and socio-economic factors. Given these limitations there is a unique opportunity for mammalian experimental models to investigate the long term effects of in utero opioid exposure, maintenance replacement therapy, as well as opioid withdrawal mitigation treatments on neurobehavioral outcomes. In the first aim we will evaluate the impact of opioid maintenance therapies (methadone and buprenorphine) on offspring, following in utero exposure to oxycodone in dams extending from conception to parturition or through pup weaning. We will also characterize the long-term behavioral impact of clinically- approved opioid withdrawal mitigation treatments, methadone and morphine, as well as buprenorphine in pups, following in utero exposure to oxycodone. In the second aim we will look to correlate changes in brain structure and volume using magnetic resonance imaging in pups following the opioid maintenance therapy in the dams as well as opioid withdrawal mitigation strategies in the pups. In the final aim we will examine whether prenatal opioid exposure and opioid maintenance or withdrawal mitigation strategies disrupt reward processing at the circuit level by examining GABAergic projections from the ventral tegmental area to the nucleus accumbens shell that we have previously shown to modulate reward behavior. Together, this approach will allow us to determine the long-term neuro-behavioral and anatomical changes that occur following in utero oxycodone-exposed pups following: 1) Opioid maintenance therapies in dams and 2) opioid withdrawal mitigation treatments in pups. We hypothesize, that this will impair learning, alter social and reward behavior, induce anxiety- and depressive- related behaviors, and reduce sensitivity to tactile and pain sensation (aim 1); decrease volume in a number of brain regions involved in reward processing and cognitive function such as the basal ganglia, thalamus, hippocampus and amygdala, change amygdalar functional connectivity as well as cause microstructural damage in the corpus callosum (aim 2); increase rewarding valance of GABAergic projection from the ventral tegmental area to the nucleus accumbens shell (aim 3). We hypothesize that exposure to buprenorphine may improve these outcomes due it’s activity at the kappa opioid receptor system. Understanding the long-term impact of oxycodone exposure in tandem with opioid maintenance therapy and opioid withdrawal mitigation strategies will allow us to explore treatment strategies and/or targets that may limit these long-term negative consequences.

NIH Research Projects · FY 2026 · 2026-05

Human induced pluripotent stem cells (hiPSCs) are a foundational technology for regenerative medicine, disease modeling, and cell-based therapies. However, the clinical translation of hiPSC-derived therapeutics is constrained by unresolved challenges in manufacturing scalability, product consistency, and long-term storage. Current production methods, such as static culture or stirred-tank bioreactors, either lack throughput or impose damaging shear forces that compromise cell viability and stemness. Additionally, existing cryopreservation strategies are not optimized for the large-volume required for centralized manufacturing and distributed clinical deployment. To address these bottlenecks, we propose to develop a modular, low-shear, perfusion-based biomanufacturing platform coupled with controlled-rate cryopreservation for scalable and reproducible expansion of hiPSCs. This R21 will establish the technical feasibility and foundational workflows for a generalizable manufacturing system suitable for diverse therapeutic applications. In Aim 1, we will engineer and optimize a multilayer, perfusion-based bioreactor system to support hiPSC expansion at clinical scales. We will define operational parameters, evaluate multiple hiPSC lines, and develop protocols for efficient harvesting and redeployment. In Aim 2, we will implement long-term culture strategies to preserve genomic stability and pluripotency across multiple passages and optimize cryopreservation workflows using cryobags and controlled-rate freezing. Post-thaw cells will be assessed for viability, genomic integrity, and differentiation potential. Successful completion of this project will yield the first integrated platform for low-shear, current Good Manufacturing Practice (cGMP)-compatible expansion and cryostorage of hiPSC-derived therapeutic products. This innovation will reduce production variability, enhance scalability, and enable rapid deployment of hiPSC-based therapies across a range of disease indications. The resulting system will serve as a flexible and translational foundation for future commercial partnerships and larger-scale studies, consistent with the high- risk, high-reward goals of the R21 mechanism.

NSF Awards · FY 2026 · 2026-05

This project supports student and early career travel to the 12th International GEOS-Chem Meeting. GEOS-Chem is an open-source global 3-D model of atmospheric composition used by hundreds of research groups around the world, including over 50 research groups in US universities. Modeling of atmospheric chemistry is a grand scientific and computational challenge because of the need to simulate hundreds of gaseous and aerosol chemical species closely coupled to each other and interacting with transport on all scales. This meeting will inform and stimulate fundamental research in modeling of atmospheric composition with links to atmospheric dynamics, biogeochemistry, and air quality. Applications of GEOS-Chem span a very wide range of atmospheric composition components, including oxidants, aerosols, carbon gases, stratospheric chemistry, mercury, persistent organic pollutants, and others. GEOS-Chem is a grass-roots community model that relies heavily on model developments and diagnostic studies by students and postdocs at universities. A central application of GEOS-Chem is as a tool to interpret atmospheric observations. Effective communication between modelers and experimenters is critical for advancing knowledge of atmospheric chemistry. 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 2026 · 2026-05

PROJECT SUMMARY AND ABSTRACT Autism spectrum disorder (ASD), a lifelong, neurodevelopmental condition defined by core behavioral symptoms encompassing social functioning, communication, restricted interests and repetitive behaviors, affects an estimated 1/36 children in the United States at a cost of $37B annually. Wide variations in ASD presentation and comorbidities affecting more than 50% of autistic individuals substantially impact diagnosis, and the planning and delivery of clinical care. Autistic children with more complex presentations due to medical and neurodevelopmental comorbidities (e.g., attention deficit hyperactivity disorder; ADHD, and/or developmental language disorder; DLD) can experience greater diagnostic and treatment delays, increasing the risk for poor developmental outcomes and quality of life. We propose to establish specificity and scalability of a promising biomarker for autism spectrum disorder (ASD) by combining innovative wearable high-density diffuse optical tomography (HD-DOT) functional neuroimaging with a Computerized Assessment of Motor Imitation (CAMI) developed by our team. Many fundamental social and communicative skills are learned through imitation and impaired imitation likely contributes to core difficulties in ASD. While movement difficulties are associated with several developmental conditions that commonly co-occur with ASD, including ADHD and DLD, deficits in motor imitation may help distinguish these overlapping conditions and capture variation relevant to underlying biology of ASD. Our team has pioneered an automated CAMI, using a brief, engaging task that can be readily scaled to clinic and home settings, with published studies showing CAMI has robust diagnostic discrimination for identifying ASD as compared with neurotypical children (NTC). However, the specificity of imitation deficits and corresponding brain mechanisms for ASD relative to other neurodevelopmental conditions has had limited study. Addressing these gaps, we propose to to establish specificity of impaired motor imitation to ASD through simultaneous assessment of motion imitation fidelity via CAMI and brain function/connectivity via HD-DOT in school-age children (6-10 years) with ASD, ADHD, DLD, and NTC. Crucially, as part of Aim 1, we will collect CAMI data using both 3D depth cameras and more readily available 2D cameras and use machine learning to build multimodal representations of movements and develop metric learning techniques to quantify motor imitation from 2D camera data alone. Additionally, we will identify brain-behavior relationships between cortical activity and connectivity with motor imitation fidelity and relate them to both diagnostic and transdiagnostic traits (Aim 2). Finally, we will extend the motor imitation brain-behavior assessments to preschool age children (3-5 years) with and without ASD (Aim 3). Across all Aims, we will assess specificity by examining associations of CAMI and HD-DOT measures with diagnoses as well as established dimensional measures of ASD, ADHD, and DLD. Our proposed study has substantial potential to profoundly improve predictive diagnostic utility over current subjective clinical assessments and thereby aid public health efforts to identify and support affected children.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT Prostate Cancer (PCa) is the most common cancer among men in the U.S., however, Black men are more likely to get and die from prostate cancer as compared to White men. Although PCa screening using Prostate-Specific Antigen (PSA) has the potential to improve outcomes, over-screening can contribute to significant harm including over-diagnosis, over-treatment, and false positives. The moderate benefits of widespread PCa screening as well as the potential harms has led to inconsistent PSA screening guidelines. This leaves the decision to screen up to each individual, ideally with men discussing the individual harms and benefits of screening with their providers before deciding whether to be screened (i.e., informed decision-making). However, evidence suggests that these nuanced decisions rarely happen. The decision to screen is especially burdensome for Black men as they are generally at higher risk for incident PCa as well as adverse outcomes. Nonetheless, even among Black men there is a lack of consistent screening recommendations. This has led to a sub-optimal situation where there is significant over-screening among older, wealthy, educated men and lower rates of screening among African American men. In ongoing research much needed strategies for PSA-based, risk-stratified or tailored screening that determines “who”, “when”, and “how often” men should be screened for PCa based on their individual risk are being developed. However, effective implementation of risk-based screening recommendations will require a thorough understanding of how men perceive screening harms and benefits. Specifically, risk-stratified screening recommendations will likely require some men to either escalate or de-escalate screening; yet little is known about how to effectively implement tailored screening decisions. These decisions will likely be even more burdensome for Black men as messaging about screening may make them more likely to favor PSA testing without the opportunity to engage in informed decision-making. Men with limited health literacy and medical mistrust may also experience additional barriers in making well-informed PCa screening decisions and navigating the healthcare system. Therefore, in this proposal we will use focus groups to characterize the perceptions, informational needs, beliefs, and knowledge of Black men regarding (1) the benefits and harms of PSA screening and (2) tailored, risk-based recommendations to escalate or de-escalate screening, while accounting for heterogeneity in health literacy and medical mistrust (Aim 1). We will then develop recommendations to enhance risk-based PSA screening decisions (Aim 2). In the future the findings of our study, coupled with risk-based screening strategies, can be used to develop a decision support tool that will aid men in making well-informed screening decisions and help improve outcomes.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Older adult populations have a disproportionate burden of lung cancer, with approximately three-quarters of patients being diagnosed at age 65 and older. Despite poor prognosis of lung cancer, advances in treatment have significantly improved survival in the past three decades. Yet, only around half of older adults with lung cancer received guidelines-concordant treatment. Furthermore, high-quality lung cancer care is not uniformly administered within older adults, and suboptimal treatment and outcomes have been well documented in selected subgroups. Medicare is a public program providing health insurance to older adults. Medicare enrollees receive their healthcare coverage through either traditional Medicare (TM) (i.e. fee-for-service) program or Medicare Advantage (MA) program that is run by private insurers and paid at capitated rates. MA enrollment has increased dramatically since 2005 with more than half of Medicare enrollees now on MA plans. These two Medicare programs have different features. TM beneficiaries are free to choose almost any providers and do not need a specialist referral. By contrast, MA plans reduce costs by limiting access to in-network providers, incentivizing primary care, and reducing utilization of unnecessary health services. MA plans offer extra benefits beyond the coverage provided by TM to address patient’s social needs. Very little is known regarding the impact of MA vs TM on cancer treatment and outcomes. Despite the more rapid growth in MA enrollment among selected subgroups, it remains unknown regarding the performance of MA vs TM in improving cancer care quality for these populations. To fill these important knowledge gaps, we will leverage large databases to create the nationally representative cohorts of lung cancer patients and adults eligible for lung cancer screening to comprehensively evaluate the delivery and quality of lung cancer care among older adults enrolled in MA and TM. Specifically, we will examine the impacts of MA vs TM on lung cancer early detection, treatment, and survival outcomes. Furthermore, we will elucidate the role of MA vs TM in lung cancer care by sociodemographic characteristics of patients. The proposed research will be the first to comprehensively evaluate early detection, treatment, and survival of lung cancer in MA vs TM beneficiaries and the contribution of MA to lung cancer care for selected subgroups. As MA enrollment among older adults has grown rapidly over the past decade, it is imperative to fully understand the impact of MA on cancer care and outcomes. The findings will inform Medicare policy optimizations and help older patients with lung cancer in choosing their health insurance coverage model.

NIH Research Projects · FY 2025 · 2026-04

Wildfires are occurring across the US and globally with potentially harmful impacts on maternal and child health. Although research into health effects specific to wildfire smoke exposure in pregnancy is nascent, a recent meta-analysis on more than 1.7 million births showed that maternal exposure during late pregnancy was linked to reduced birth weight and preterm birth. However, the short and long-term effects of repeated wildfire smoke exposure during pregnancy on maternal and fetal health outcomes have not been investigated in depth, nor are any molecular mechanisms responsible for such effects well understood. Therefore, there is an urgent need to understand the how wildfire smoke exposure affects health and wellbeing. One hypothesized mechanism to facilitate biological communication from pollutants inhaled in the lung to distal organs and tissues is through extracellular vesicles (EVs). EVs contain a variety of biologically active molecules including microRNAs (miRNAs) which are small ~22 nucleotide-long noncoding RNA molecules. EV-miRNA might be the ideal candidates to mediate effects of wildfire smoke exposures on pregnancy because they can be produced by the respiratory system where the initial exposure occurs and then enter the circulation to affect distant tissues and organs. We hypothesize that prenatal exposure to wildfire smoke triggers a biological response that can be measured in EV-miRNA, and that these wildfire smoke-related biological signatures are negatively associated with fetal and infant growth. We will additionally investigate the interplay between smoke exposure and miRNA signatures with neighborhood characteristics, including housing, infrastructure, and other factors that may modify effects on fetal and infant growth. We will examine this hypothesis in 466 participants in MADRES—a cohort representative of the population living in Los Angeles, CA – in the following aims: Aim 1) Identify unique EV-miRNA transcriptomic signatures of wildfire smoke across pregnancy and the biological pathways associated with their predicted gene targets in a population of 466 pregnant participants with 666 maternal biospecimens. Aim 2) Evaluate the influence of wildfire-associated EV-miRNA signatures on ultrasound-measured fetal growth, infant birthweight, body composition and child growth through age 7. We will additionally evaluate effect modification by sex of child and neighborhood characteristics. Aim 3) In exploratory analyses in a subset of 96 mother/child pairs, we will test whether wildfire smoke exposures affect newborn miRNA levels in cord blood and further investigate the correlation of EV-miRNA expression profiles between mother and infant. Findings from this study may inform future screening, diagnostic, or treatment, interventions by helping us understand the biological effects of wildfire smoke.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Steroid-resistant nephrotic syndrome is a devastating pediatric kidney disorder characterized by proteinuria, glomerulosclerosis, and progression to end-stage renal failure. A significant fraction of childhood-onset SRNS cases are caused by mutations in NPHS2, which encodes Podocin—a membrane scaffolding protein essential for maintaining the integrity of the glomerular filtration barrier. Despite Podocin’s critical role in kidney function, its molecular architecture, assembly mechanisms, and the structural consequences of disease-causing mutations remain unknown. This gap in knowledge hinders the development of targeted therapies for steroid-resistant nephrotic syndrome. This project aims to determine the structural organization and mechanistic function of Podocin in native membranes and to identify strategies to restore its activity in disease contexts. We will apply a detergent- free, vesicle-based cryo-electron microscopy platform—developed by our group—to resolve the full- length structure of Podocin at near-atomic resolution. Building on recent breakthroughs in visualizing related SPFH-domain proteins, including Flotillin and Stomatin, we hypothesize that Podocin assembles into higher-order oligomers that scaffold signaling domains at the slit diaphragm. Using cryo-EM, site- directed mutagenesis, and functional assays, we will determine how steroid-resistant nephrotic syndrome-associated mutations disrupt Podocin oligomerization, membrane targeting, and function. In parallel, we will develop a structure-guided discovery pipeline to identify therapeutic strategies that rescue defective Podocin variants. This includes high-content imaging assays, DNA-encoded library screening for small-molecule stabilizers, and de novo peptide design targeting key oligomerization interfaces. Candidate rescue agents will be validated structurally and functionally in cell models and podocyte systems. This interdisciplinary project integrates structural biology, membrane biophysics, kidney cell biology, and drug discovery to address an urgent unmet need in pediatric nephrology. The outcomes will provide foundational insights into the molecular basis of steroid-resistant nephrotic syndrome, define new principles of membrane domain organization, and pave the way for the development of targeted therapeutics for patients with NPHS2-linked kidney disease.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT While endovascular thrombectomy (EVT) has revolutionized the treatment of acute ischemic stroke caused by large vessel occlusion (LVO), 54% of patients still experience severe disability or death. This variability in outcomes highlights a critical gap in stroke management, which primarily focuses on restoring blood flow but fails to address the downstream molecular events that drive continued neuronal injury. Decades of preclinical research have sought to bridge this gap, identifying over 1,000 potential cerebroprotective drug targets. However, the failure to translate these findings into clinical success raises concerns about the validity of cellular and animal models in stroke research. The overarching goal of this study is to identify and validate cerebroprotective drug targets in humans by directly sampling blood within the ischemic vasculature during active ischemia. To achieve this, we will leverage the high EVT volume at Barnes-Jewish Hospital/Washington University School of Medicine (WUSM) and the endovascular approach of the intervention to collect 40 paired periprocedural arterial blood samples: 1) Pre-thrombus: From the femoral artery at the time of groin puncture; 2) Post-thrombus: From distal to the occluded cerebral vessel, obtained via microcatheter advancement through the thrombus on first pass. I hypothesize that post-thrombus blood, sampled adjacent to ischemic tissue, will reveal a cellular and molecular milieu distinct from peripheral circulation, providing clinically relevant, human-specific cerebroprotective drug targets. This hypothesis and the feasibility of this collection technique are supported by a pilot study conducted during my NINDS T32 vascular neurology fellowship at the University of Cincinnati. Further demonstrating feasibility, pre/post-thrombus sample collection is already underway as part of my KL2 Career Development Award at WUSM, through the establishment of a deeply phenotyped, prospective EVT biorepository. Supported by WUSM’s vast research community, this study will: 1) Define ischemic cellular transcriptomes in post- vs. pre- thrombus arterial blood samples using single-cell RNA sequencing; 2) Determine whether a unique post- thrombus gene expression signature is associated with clinical neurologic improvement or deterioration in LVO patients; 3) Evaluate the drug target potential of identified gene expression signatures using network-based analyses and bioinformatics (exploratory). The data generated will be widely shared to accelerate drug target discovery and has the potential to make a significant impact by identifying highly translatable therapeutic targets. This study will provide critical protected time, funding, and mentored guidance from leaders in cerebrovascular injury, computational transcriptomics, and neuroimmunology, equipping me with the expertise to achieve my long-term career goal: Establish an independent, NIH-funded research program focused on bridging the translational gap in stroke and delivering effective cerebroprotective therapies to clinical practice. Additionally, the robust dataset generated by this study, combined with my KL2 biorepository, will lay the foundation for future independent multi-omic grant proposals that I plan to submit in the final years of this award.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Genital malformation including hypospadias represents the second most common male birth defect after cardiac defect. In the past 50 years, hypospadias incidence has doubled along with other male reproductive abnormalities. It is suspected that fetal exposure to endocrine disruptors may have contributed to this increase. However, the etiology of hypospadias is still largely unclear. Both environmental and genetic factors are involved. Thus, there is an urgent need to understand genetic pathways regulating urethral closure as well as lower urinary tract development in general. Unfortunately, insufficient prospective screening tools have prevented the rapid identification of causative genes. We have recently developed a streamlined forward genetic screening technology combining in vivo and in vitro approaches to rapidly identify crucial regulators of genital masculinization and lower urinary tract development. As a result, we have identified 31 high priority candidate transcription factors downstream of androgen receptor, regulating genital masculinization. In light of recent discovery that an extra-genital cell population migrates into the developing genitalia and is required for urethral closure, this proposal will use two purified GT mesenchymal populations to increase the cellular and functional resolution of our established high-throughput screening system. We will use these novel screening systems to reevaluate the function of transcription factors during urethral closure. In Aim I, we will use two tissue-specific mouse Cre lines to isolate pure populations of mesenchymal cells in the developing GT and test their cellular response to androgen stimulation. In Aim II, we will perform a proof-of-concept screen for transcription factors governing either their proliferation or migration. Together, these studies should greatly accelerate the discovery progress for master regulators of urethral closure. Our long-term goal is to use mouse molecular genetics to understand the process of urethral closure and the etiology of genital malformations, such as hypospadias.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT. Viral triggers of autoimmune disease remain poorly understood and have been hypothesized to contribute as initial triggers of the immune disturbances that underlie clinical autoimmunity as well as promoters of disease. Human Roseoloviruses, Human Herpesvirus (HHV)-6 and 7, have been associated with several autoimmune diseases notably encephalitis, and multiple sclerosis (MS). Due to high species-specific tropism, human herpesviruses are difficult to study in a controlled environment, and their relationship with the development of these disorders remains elusive. Recently however, the murine roseolovirus (MRV) was identified and found to be a close homolog of HHV-6 and 7. MRV is a thymotropic virus that causes transient, severe thymic atrophy with the most pronounced loss occurring in CD4/CD8 double-positive (DP) and CD4 single-positive (SP) thymocytes. Single-cell RNA sequencing data shows that CD4 SPs, DPs and double negative (DN) thymocytes as well as medullary thymic epithelial cells (mTECs) can support productive infection of MRV. Neonatal infection of mice with MRV causes autoimmune gastritis (AIG) in adulthood. CD4 T cells are both required and sufficient for AIG development in this model. MRV infections also results in loss of AIRE transcripts in mTECs, and development of autoantibodies to several tissue antigens targeting almost all organ systems. Additionally, type I interferon (IFN) signaling is required for development of AIG in neonatally infected mice. The goal of this study is to understand the role of type I IFN signaling in auto-immune gastritis development in the setting of neonatal MRV infection. We hypothesize that type I IFN is a major contributor in the disruption of central tolerance, specifically leading to alterations in T cell selection and development of autoreactive T cells, as well as an aberrant T regulatory cell (Treg) response. I will investigate whether type I IFN is required for the development of autoreactive T cells and whether type I IFN leads to disruptions in Treg development. Using a unique model of virus-induced autoimmunity, our study has the potential to shed light on the infectious triggers of the immune disturbances observed sometimes years prior to clinical symptoms, providing insight into the early mechanisms underlying autoimmune disease onset. As an MD/PhD student, my long-term goal is to become a physician-scientist leading a research lab in dermatology. Completion of this project will equip me with a strong foundation at the intersection of immunology, virology, and autoimmunity, fields that often converge in skin-related clinical presentations. My robust training plan at WashU in St Louis, one of the nation's leading MD/PhD programs integrates strong mentorship, rigorous coursework, independent study, and participation in research meetings ranging from local to international. This tailored approach is designed to support the successful execution of my research proposal and to position me for long-term success in achieving my career goals.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Lung cancer is the leading cause of cancer death in both men and women, with non-small cell lung cancer (NSCLC) comprising about 85% of cases. Standard-of-care for locally advanced, non-metastatic NSCLC includes cytotoxic chemotherapy, external beam radiation therapy (XRT), and immunotherapy. Despite noted benefits, many patients do not respond favorably, and a majority who initially respond experience progression, underscoring the urgent need for improved treatment strategies. We propose a transformative approach using antibody-drug conjugates (ADCs) for targeted delivery of cytotoxic drugs that act as radiosensitizers, leveraging our breakthrough discovery of radiation-inducible antigens. Specifically, we identified Tax-interacting protein 1 (TIP1) as significantly upregulated on NSCLC cells post-XRT, positioning TIP1 as a prime target for ADCs. Preliminary data demonstrate that anti-TIP1 antibodies, which undergo endocytosis and deliver payloads specifically to tumor cells, dramatically enhance XRT efficacy. Our second-generation anti-human TIP1 ADCs feature a human antibody, an advanced drug-linking strategy to minimize premature drug release, and a highly potent payload, ensuring a robust therapeutic index. We hypothesize that these ADCs will markedly enhance the therapeutic index of XRT over chemotherapy and significantly improve the durability of immune checkpoint blockade responses, potentially transforming NSCLC treatment. Aim 1 will test the hypothesis that radiosensitization by anti-TIP1 ADCs in NSCLC is independent of mutational status. We will assess TIP1 upregulation, enhanced drug delivery, and therapeutic efficacy across NSCLC cell lines and patient-derived xenografts (PDXs), stratifying patients to identify those most benefit from ADC therapy. Aim 2 will investigate how anti-human TIP1 ADCs improve XRT-induced tumor immunity and response to immunotherapy. We will examine the impact of the ADC+XRT combination on anti-tumor immunity and response to immune checkpoint blockade in immunocompetent mice and genetically engineered mouse models (GEMMs), providing a direct comparison to chemotherapy + XRT. Aim 3 will assess the pharmacokinetics (PK), maximum tolerated dose (MTD), and payload release of anti-human TIP1 ADCs in normal tissues. We will conduct these evaluations in immunocompetent mice, leveraging the near-identical similarity between mouse and human TIP1. This research can potentially revolutionize the integration of ADCs with XRT in NSCLC, significantly improving the therapeutic index and efficacy of XRT. It will also provide critical insights into how ADC/XRT combinations modulate the tumor microenvironment and enhance anti-tumor immunity, offering new avenues to bolster checkpoint blockade responses. Our preclinical evaluation of human TIP1-ADCs will pave the way for clinical development, presenting a groundbreaking strategy for NSCLC treatment that could extend survival and improve the quality of life for patients.