Case Western Reserve University

NSF Awards · FY 2026 · 2026-10

Foundation models are large artificial intelligence (AI) systems trained on vast amounts of data to perform a wide range of tasks, including answering questions, generating content, and assisting decision-making. These models are increasingly used in areas that affect everyday life, such as healthcare, education, and environmental planning. However, despite their impressive capabilities, they often rely on patterns and correlations in data rather than true causal relationships. This limitation can lead to unreliable or misleading outputs, especially in high-stakes situations. For example, a model may incorrectly assume that one factor causes another simply because they frequently appear together in data. This project addresses this critical challenge by enabling foundation models to better understand and use causal knowledge, which describes how one factor directly influences another in the real world. By improving the ability of these models to reason about cause and effect, the project aims to make them more reliable, transparent, and aligned with human reasoning. The results will support safer and more effective use of AI in important societal domains, strengthen decision-making in complex environments, and contribute to education and workforce development by training students in emerging areas of trustworthy AI. This project develops a systematic framework for understanding, leveraging, editing, and applying causal knowledge in foundation models, organized into four complementary thrusts. The first thrust introduces methods to interpret causal relationships embedded within large-scale models by analyzing internal components that encode causal knowledge across language, vision, and multimodal systems. The second thrust designs approaches to incorporate external causal knowledge into model reasoning, improving performance in tasks such as question answering, causal reasoning, and video understanding. The third thrust establishes techniques for editing causal knowledge within models, enabling targeted updates to specific relationships while preserving overall model performance and consistency. The fourth thrust focuses on empirical evaluation and application of the proposed methods across diverse application domains, including healthcare, materials science, and environmental systems. The project integrates research with education through curriculum development, student mentoring, and outreach activities, and produces open-source tools and resources to support broader adoption. Together, these efforts advance the development of interpretable, controllable, and generalizable foundation models grounded in a causal perspective. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2026 · 2026-07

This award funds the research activities of Professor Claire Zukowski at the University of Minnesota Duluth. Quantum physics has successfully described the constituents of matter at subatomic scales. On the other hand, Einstein’s theory of gravity dominates the behavior of matter at the largest known scales in our universe. While it is well-tested at large scales, gravity is the only known force for which we do not know the quantum description. There are regimes where one is needed: for instance, deep inside a black hole or shortly after the Big Bang, when our entire gravitating universe was compressed within a tiny region. A theory of quantum gravity aims to fill in these gaps in our fundamental understanding of the universe, but is most tractable in models that do not describe our actual universe. In this project, Professor Zukowski will study quantum gravity in a setting that approximates our known universe. The research will advance the national interest by promoting the progress of science through an understanding of physical laws. The work will also have significant broader impacts. Professor Zukowski will train both undergraduate and master’s students in this field of research, providing crucial support for their education and career development. She will also give lectures aimed at high school students and the general public about recent developments in quantum gravity. More technically, Professor Zukowski will study quantum gravity in de Sitter spacetime. Using standard techniques in holography as a starting point, she will apply quantum information theoretic tools such as modular Berry transport and complexity to probe bulk geometry. While traditional dS/CFT has presented challenges for generalizing holography beyond asymptotically AdS spacetimes, new avenues are opened by recent developments in Chern-Simons gravity. Professor Zukowski will use these methods to compute new quantum observables for de Sitter. Finally, the project will also connect to cosmology through a further study of the landscape. Performing general warped compactifications and applying a new bootstrap technique for compactifications will constrain the low-energy landscape for quantum gravity. 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 · 2026-06

Project Summary: Ewing sarcoma is a devastating pediatric malignancy characterized by pathological EWSR1-ETS fusion transcription factors and remains devoid of molecularly targeted therapies. Through unbiased small molecule screening, transcript-level correlational analyses, and mechanistic validation, I have identified a class of compounds—FADS2-dependent cytotoxins (FDCs)—that selectively kill Ewing sarcoma cells by co-opting the oxidative catalytic activity of fatty acid desaturase 2 (FADS2). Mechanistic studies suggest these agents act as non-native substrates that induce a gain-of-toxic-function effect on FADS2, leveraging its catalytic activity to generate superoxide and drive redox collapse. There is a direct positive correlation between FADS2 expression level and increased toxicity to FDCs. Notably, Ewing sarcoma exhibits uniquely and consistently high FADS2 expression across established cancer cell lines and patient-derived tumors, with comparably low expression in non-diseased tissue—suggesting an exploitable therapeutic window. Yet, the mechanistic underpinnings of FDC- induced cytotoxicity and their translational potential in Ewing sarcoma remain uncharacterized. This proposal tests the central hypothesis that aberrantly high FADS2 expression creates a lineage-specific vulnerability that can be pharmacologically exploited with FDCs. In Aim 1, I will define the requirement of FADS2 expression in mediating FDC toxicity using genetic loss-of-function. In Aim 2, I will define the oxidative intermediates formed in response to FDC treatment in a FADS2-dependent manner. In Aim 3, I will evaluate the in vivo efficacy of FDCs in Ewing sarcoma orthotopic xenograft models. Together, these studies will establish a mechanistic framework for FADS2-dependent cytotoxicity, provide preclinical rationale for targeting this metabolic liability in Ewing sarcoma, and advance a novel therapeutic strategy for a disease with urgent unmet clinical need.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Retinal degeneration is a leading cause of blindness, with mounting evidence implicating environmental factors such as blue light (430–470 nm) exposure in its progression. A key pathological mechanism involves the phototoxic byproduct A2E, which accumulates in retinal pigment epithelium (RPE) cells and undergoes photoactivation by blue light to generate reactive oxygen species (ROS). These ROS, in turn, drive lipid peroxidation (LPO) of polyunsaturated fatty acids (PUFAs), producing electrophilic metabolites that contribute to retinal injury. Our recent studies have identified epoxyketooctadecenoic acids (EKODEs) as prominent LPO byproducts formed via A2E-induced oxidation, with the ability to covalently modify proteins via cysteine adducts. This proposal investigates the hypothesis that blue light–activated A2E promotes EKODE formation, which in turn inhibits lecithin retinol acyltransferase (LRAT), a critical enzyme in the visual cycle responsible for regenerating the light-sensitive chromophore. Disruption of LRAT function is strongly associated with severe visual dysfunction and photoreceptor degeneration. By directly linking A2E-mediated oxidation to the generation of EKODEs and their inhibitory effects on LRAT, this study will address a critical gap in our understanding of blue light–induced retinal damage at the molecular level. To test this hypothesis, Aim 1 will define the wavelength-dependent conditions under which photoactivated A2E catalyzes LPO and promotes EKODE formation. Using novel LC-MS/MS methods, we will characterize these lipid oxidation products in vitro and in biologically relevant models, such as bovine eyecups. Aim 2 will investigate the impact of EKODEs on LRAT activity, employing proteomic approaches to detect and map EKODE-protein adducts in vitro and in vivo. By elucidating how blue light exposure, in the presence of A2E, leads to electrophilic EKODE production and LRAT inhibition, this research will provide novel insights into the biochemical pathways driving retinal degeneration. The findings could inform the development of targeted interventions, such as antioxidant therapies or optical filters, to mitigate blue light–induced retinal damage and preserve visual function.

NIH Research Projects · FY 2026 · 2026-06

Project Summary/Abstract Each year, more than three million adults aged 35 and older are admitted to intensive care units (ICUs) in the United States. Most require a surrogate decision-maker (SDM) to make timely, emotionally charged treatment decisions. Often unprepared for this responsibility, SDMs frequently experience significant psychological distress that can impair their ability to make informed, value-congruent decisions. Long-term psychological consequences, such as post-traumatic stress disorder (PTSD) and decision regret, often follow these acute effects. Despite decades of research, few evidence-based and scalable interventions effectively address the SDMs’ emotional needs during ICU stays. This project will evaluate the efficacy and mechanisms of REFRAME, a brief, self-directed, tablet-based intervention grounded in cognitive reappraisal theory. REFRAME is designed to help SDMs recognize, reinterpret, and regulate their emotional responses in real time as they navigate high-stakes decisions. The intervention includes interactive psychoeducation and emotional assessments, guided strategy selection, emotionally relevant ICU scenarios, and structured planning to apply reappraisal techniques to real-world decision-making. In a two-arm, parallel-group randomized controlled trial, 387 SDMs of critically ill patients will be enrolled and randomized to either the REFRAME intervention or an attention-matched informational support (IS) control condition. Participants will complete standardized outcome measures at baseline (T0), 24-48 hours post- intervention (T1), 24-48 hours post-T1 (T2), and 90 days post-baseline (T3). Aim 1 will evaluate the effects of REFRAME on depressive symptoms (primary outcome at T2) and PTSD symptoms and decision regret (secondary outcomes at T3). Aim 2 will examine differences between groups in state emotion regulation (cognitive reappraisal and expressive suppression) at T1. Aim 3 will test whether changes in state emotion regulation mediate the effect of the intervention condition on psychological outcomes. By targeting a core, modifiable mechanism—emotion regulation—this trial aims to enhance psychological resilience, decision-making quality, and overall family-centered outcomes. The study findings will guide the development of scalable, mechanism-focused interventions to alleviate mental health burdens and improve care experiences in critical care and other surrogate decision-making contexts.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY: The rural village of East Palestine, Ohio and its Surrounding Communities (EPSC) have faced an environmental disaster since February 2023 when a Norfolk Southern freight train derailed, releasing over 2,000,000 gallons of hazardous chemicals (including vinyl chloride) into the air, soil, and water. Emergency responders purposively ignited the volatile chemicals to prevent a potential explosion, in turn releasing even more carcinogenic toxicants arising from combustion into the community. The definitive extent of the derailment, including health impacts and repercussions from community and governmental response, remains to be seen. However, early evidence suggests that residents have faced economic hardships, ongoing health problems, and eco-psycho-social disruptions in the wake of the derailment. This research explores the disaster’s emergency management system and existing gaps within it to inform best practices for future disaster response in marginalized communities. NIEHS’ current strategic plan establishes advancing evidence-based health promotion interventions, expanding health-equity disaster research, and integrating social sciences for effective translational science as key themes and priorities necessary to progress health and the field of environmental health sciences; these priorities have informed this fellowship’s research design and training plan. This research design adopts a pragmatic explanatory sequential mixed methods approach. This study will provide insights as to how emergency management networks in rural and border communities adapt, or fail to adapt, during emergency response. The central hypothesis of this proposal is that differences between planned vs. actual organizational emergency response networks indicate beneficial or burdensome adaptations that should be reflected in policy. Aim I will create and analyze interorganizational social networks for both planned and observed emergency management in EPSC to reveal policy-to-practice gaps. Aim II investigates how the structure of the observed emergency response network evolved to reveal temporal shifts in disaster management efficiency. Aim III presents the network structures and analyses from previous aims to key stakeholders in the network to contextualize network differences and dynamics through key informant interviews. The expected outcomes of this research are: (1) a comprehensive understanding of how response organizations functioned before, during, and after the East Palestine train derailment; and (2) actionable recommendations for enhancing emergency response infrastructure in rural or border communities facing environmental disasters. The combined educational and research support from Case Western Reserve University, my multidisciplinary team of mentors, and my thorough training plan will prepare me to complete this translational research rural and border communities as well as provide the skills necessary for me to thrive as a disaster epidemiologist.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Mitochondria are dynamic organelles that undergo cycles of division and fusion. Mitochondrial division (MD) is essential for mitochondrial quality control, transport, distribution, and inheritance. Defects in MD underlie various neurological disorders, including Alzheimer’s, Parkinson’s, and Huntington’s diseases, as well as cardiovascular disease and cancer. While the mechanochemical GTPase dynamin-related protein 1 (Drp1) is key to MD, the molecular mechanisms governing Drp1 function in mitochondrial membrane remodeling remain poorly understood. Recent studies indicate that Drp1 is both structurally and functionally autoinhibited, necessitating an essential role for binding partners in alleviating this autoinhibition. Here, we will investigate the distinct allosteric nodes of functional control exercised by the protein partners GIPC1, MiD51, and Dynamin 2 (Dyn2) on Drp1-catalyzed MD. This grant application aims to address several unknown fundamental issues essential for understanding Drp1-catalyzed MD. These include: 1) understanding the structural basis and mechanism of autoinhibition by the intrinsically disordered Drp1 C-terminal Short Linear Motif, and its alleviation by GIPC1, 2) investigating the mechanisms involved in the MiD51-directed conformational transition of Drp1 from the autoinhibited form in solution to the assembly-competent form on membranes, including the role of the putative interface-4 in MiD51-directed Drp1 co-assembly, and 3) studying the mechanisms of Dyn2 in regulating Drp1 assembly-disassembly dynamics on membranes to improve membrane fission efficacy. We will combine mutagenesis and X-ray crystallography with cutting-edge cryo-EM, and multiple independent fluorescence spectroscopic and imaging techniques to address these aims. Successful outcomes of this research project will provide (i) a fundamentally improved understanding of the mechanisms underlying Drp1-catalyzed MD, and (ii) a molecular foundation for the design of drugs and therapeutics that can beneficially modulate MD in various diseased states.

NIH Research Projects · FY 2026 · 2026-05

Project Summary: Annually, millions of patients are diagnosed with autoimmune disorders. The majority of these are treated with global immune suppressants. These drugs often tip the balance from autoimmunity to immune suppression, triggering undesirable, systemic side effects. Previously, it had been established in literature that Exportin-1 (XPO1) is a novel target for the inhibition of T cell activation. XPO1 is canonically recognized as a nuclear cargo export protein where it shuttles cargo from the nucleus into the cytoplasm. Recently, it has been reported that XPO1 also plays a critical role as a chromatin factor. XPO1’s chromatin function can be inhibited with novel molecules coined “Selective Inhibitors of Transcriptional Activation” (SITAs). Mechanistically, it has been determined that these SITAs covalently bind to the C528 position of XPO1 in the same binding pocket as known nuclear export inhibitors called “Selective Inhibitors of Nuclear Export” (SINEs), as exemplified by the FDA approved inhibitor, Selinexor. While SITAs and SINEs covalently engage the same pocket, it is mechanistically unclear how and why these reported SITAs have the disparate phenotypic effect of inhibiting T cell activation compared to established SINEs which inhibit nuclear export. This proposal seeks to test the central hypothesis that the SITAs’ phenotypic deviation from SINEs stems from the rapid reversion of the covalent bond formed by SITAs in the C528 pocket.

NIH Research Projects · FY 2026 · 2026-05

Project Summary HIV drug resistance represents a growing and underappreciated threat to the U.S. HIV response. Although more than 1.2 million people are living with HIV in the U.S., only about 60% achieve durable viral suppression, and resistance is a major contributor to treatment failure and regimen switching. Current resistance testing relies on centralized, PCR and sequencing-based platforms that are expensive, slow, and available only at specialty laboratories, requiring multiple clinic visits and highly trained personnel. As a result, same- day, resistance-informed treatment decisions are rarely possible, even in major U.S. cities, and are essentially inaccessible in rural areas, mobile care units, and safety-net clinics serving areas where the epidemic is increasingly concentrated. These gaps most severely affect communities already carrying the highest burden of HIV incidence and treatment failure in the U.S. Without affordable, accessible, point-of-care (POC) resistance testing, the durability of ART and the success of the national Ending the HIV Epidemic initiative are at risk. Our project aims to develop HIV-CRISP to addresses this critical gap by developing a cost-effective, same- visit “test-and-switch” POC device that integrates CRISPR-based nucleic acid detection with a bioinspired microfluidic chip (CamoChip). This fully automated platform enables simultaneous detection of HIV viral load and drug resistance to four major ART classes (NRTIs, NNRTIs, INSTIs, and PIs) during a single clinic visit. By empowering providers to make immediate, resistance-informed treatment decisions, HIV-CRISP reduces delays in therapy initiation or modification and minimizes the risk of treatment failure. The project is structured around three specific aims: Specific Aim 1: optimize a PAMmer-assisted CRISPR system for accurate detection and profiling of HIV drug resistance mutations; Specific Aim 2: enhance CamoChip readout technology for rapid, multiplex POC testing; and Specific Aim 3: integrate these components into a user-informed POC device and validate its performance against standard methods with clinical samples. Each aim not only drives independent scientific advances but also converges on the development of a transformative POC diagnostic. HIV-CRISP represents an innovation in HIV diagnostics with broad public health significance. This platform supports wide access to high-quality HIV care in under-resourced settings across the U.S. and globally, while also providing a foundation adaptable to other infectious diseases and health conditions.

NIH Research Projects · FY 2026 · 2026-05

Abstract The estrogen receptor (ER or ERα) plays a fundamental role in breast cancer through complex molecular mechanisms involving its N-terminal transactivation domain (NTD), DNA-binding domain (DBD), and ligand- binding domain (LBD). Understanding their structural dynamics is crucial for developing next-generation ER- targeted therapeutics. Our research employs advanced biophysical techniques to decode two fundamental aspects of ER regulation. Project-1 will characterize the structural properties of the NTD through nuclear magnetic resonance spectroscopy and small-angle X-ray scattering (SAXS), generating comprehensive structural insights. Project-2 will examine the dynamic interactions between DBD and LBD using cryo-electron microscopy combined with solution-state SAXS analysis, revealing how various factors influence domain communication. These studies will establish a detailed framework for understanding ER regulation in normal and disease states, with broad implications for the nuclear receptor family. Our data-driven computational strategy will illuminate new molecular mechanisms underlying receptor function. The methodological advances from this research will enhance our understanding of protein dynamics and domain interactions across the nuclear receptor family, potentially leading to innovative therapeutic strategies for hormone-dependent cancers.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY In many chronic inflammatory diseases, the vascular endothelium becomes pathologically permeable due to conditions like angiogenesis and production of growth factors and inflammatory cytokines (e.g. histamine, bradykinin, etc.). In cancer, this process can be exploited for delivery of nanoparticles to tumors– via the enhanced permeability and retention (EPR) effect. However, nanoparticle-based therapeutics have led to inconsistent results in patients. This is due to many factors, with a main one being heterogeneous tumor vascular architecture both between patients and within a single tumor. Transport of the nanoparticle to the tumor and into the parenchyma is complicated by uptake by the immune system, ineffective margination, and inefficient extravasation. Guidance is needed to inform clinicians on what therapies may be most effective for each patient. Effective guidance could reduce healthcare costs and negative side effects of medication. An inexpensive, safe, non-invasive, and real-time imaging method may be capable of categorizing the extent of vascular permeability in tumors and once validated, personalize therapeutic regimens for patients. Such a tool could be used not only for tumors, but for all diseases involving pathologically permeable vasculature. With this goal in mind, the objective of the proposed research in this application is to develop a series of contrast-enhanced ultrasound (CEUS) imaging biomarkers that correspond to increased vascular permeability in target tissue and use these biomarkers to work toward development of a method for predicting therapeutic nanoparticle accumulation in tumors. This method will build upon dynamic CEUS protocols used clinically with microbubbles (MBs). However, since MBs are approximately the same size as erythrocytes, a new agent must be developed for this application. We propose to develop stable gas-core nanoparticles, also known as nanobubbles (NBs), for this application. NBs are ~100-300 nm in diameter, visible with CEUS methods, and have been shown to extravasate into the tumor parenchyma. The use of clinical ultrasound in developing this method will ensure that eventual translation to patients is safe, cost-effective, non-invasive, and widely accessible. Our strong preliminary evidence supports the hypothesis that initial NB kinetics in tumors measured by US are an excellent indicator of tumor vascular permeability and can predict nanomedicine accumulation in tumors. We will further develop and apply the technique to establish a tool which can be used to assess tumors prior to treatment and establish whether they would be susceptible to nanomedicine-based chemotherapy. The approach has four aims: We will first optimize the NB formulation and develop effective image acquisition techniques. Next, we will validate that nanobubble-enhanced US imaging parameters correlate with vascular permeability of tumors bubble kinetics. Once the technique is validated, we will apply it to predict the extent of nanoparticle accumulation in tumors. Finally, we will use the imaging data to predict tumor susceptibility to Doxil® in treatment of mice and orthotopic tumors in rabbits, as a large animal validation. The research will yield: 1) a new tool to examine the fundamental phenomenon of enhanced permeability and retention in tumors in real time and 2) a foundation for development of a comprehensive predictive clinical tool for selection of cancer patients whose tumors are suitable for nanoparticle-based chemotherapeutics. Both factors are crucial for expanding the role of nanomedicine in cancer treatment.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY: People with HIV (PWH) face persistent low-grade inflammation, pro-active blood clotting mechanisms, and a twofold higher risk of cardiovascular disease despite effective anti-HIV treatments. A recent clinical trial showed that statins reduce cardiovascular disease risks by up to 35%, but PWH still face higher risks than non-HIV individuals, revealing gaps in our understanding cardiovascular disease pathogenesis. The persistence of cell free hemoglobin (CFH) above normal physiological thresholds in virologically controlled PWH may be an underappreciated factor contributing to the chronic immune activation and a pro-thrombotic state. To date, a comprehensive knowledge of the causes and pathobiological significance of red blood cell-derived extracellular vesicles (rEVs) containing cell-free hemoglobin in PWH remains elusive. Furthermore, the potential impact of these vesicles on endothelial cells and platelets - resulting in endothelial dysfunction and platelet hyperreactivity - is inadequately understood, despite their association with an increased likelihood of cardiovascular disease pathogenesis in hemolytic anemias without HIV. This proposal centers on the hypothesis that extracellular vesicles, particularly rEVs, might be an additional contributor to endothelial dysfunction and platelet activation in PWH. By addressing this, this study aims to shed light on a previously less recognized CVD risk factor in PWH and would reveal novel translational approaches to mitigate endothelial dysfunction and chronic inflammations. Our central innovation lies in investigating the ability of rEVs and rEV- associated cell free hemoglobin to trigger endothelial and platelet responses, a novel focus that could fill significant knowledge gaps regarding residual cardiovascular disease. In this project’s we initially plan to quantify and characterize rEVs and rEV-associated CFH in PWH and the uninfected control samples and to examine their capacity to elicit endothelial dysfunction and platelet activation by ex vivo experiments. The study will explore correlations between rEV-associated cell free hemoglobin levels and chronic inflammation in PWH. It will investigate whether rEVs cause endothelial dysfunction through free radicals, reactive oxygen species, and TLR4 signaling. Specific Aim 1 involves isolating and analyzing rEVs from PWH and non-HIV controls to test if PWH have higher rEV-bound CFH levels, along with assessing pro-inflammatory cytokine levels. In Specific Aim 2, ex vivo studies will use human aortic endothelial cells and gel-purified platelets to examine rEV-driven dysfunction and activation using gene sequencing, flow cytometry, and Seahorse metabolic assays. The study will leverage de-identified plasma from the Center for AIDs Research sample repository at Case Western Reserve University. We aim to initiate larges insightful studies in the future based on the knowledge gained from this exploratory study. This project aims to uncover residual cardiovascular disease risks in PWH through a retrospective case-control study of 124 plasma samples, offering strategies for clinical intervention to benefit both PWH and non-HIV populations. The findings will broaden our understanding of cardiovascular risks in other systemic, diseases like sickle cell anemia.

NSF Awards · FY 2026 · 2026-04

The field of computational biology is essential for advancing national health, prosperity, and welfare by driving innovation in medicine, agriculture, and biotechnology. This project supports U.S.-based student participation in the 30th Annual International Conference on Research in Computational Molecular Biology (RECOMB 2026). By providing travel fellowships to graduate and undergraduate students, the award ensures that the next generation of scientists can engage with global experts and cutting-edge research. This initiative seeks to immerse students in cutting-edge work, strengthen their research skills, and expand their professional networks, thereby amplifying the impact of their future contributions to science and society. The goal of this award is to facilitate the professional development of ten students specializing in computational biology through travel support to RECOMB 2026 in Thessaloniki, Greece. The conference scope encompasses the intersection of mathematical, statistical, and biological sciences, featuring peer-reviewed presentations on theoretical advances in molecular biology. Selection for the fellowships is based on a merit-based process that prioritizes student authors of accepted research papers and posters, ensuring high-quality scientific exchange. Participating students will engage in keynote sessions and research presentations, allowing for the dissemination of new computational methods across institutions. The project aims to accelerate the research trajectories of the recipients by providing direct exposure to the latest algorithmic developments and fostering professional networks with established investigators in the field. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2026-04

Project Summary - Current treatments for Pv are limited, highlighting the need for new therapies targeting both liver and blood stages. Relapsing parasites account for up to 80% of infections and disease, establishing a global reservoir that is difficult to eliminate with current treatments. Blocking liver-stage infections is the most effective strategy to prevent dormant parasites. A human monoclonal antibody (humAb826827) targets Pv apical membrane antigen1 (AMA1), blocking both liver and blood stage Pv infections. Large language models and binder designs will be used to develop novel human monoclonal antibodies targeting Pv invasion ligands, which will be tested in vitro with Pv clinical isolates. This strategy adapts methods used in enhancing anti- EGFR mAb, Cetuximab, for cancer therapy. Three approaches will be used to design mAbs: enhancing existing mAbs, designing new mAbs, and optimizing current mAbs. Enhanced and novel mAbs will be tested using a collaborative network in Cambodia. The computational approach avoids the bottleneck of isolating PBMCs from Pv-infected individuals. Developing effective mAb candidates requires optimization across multiple dimensions, including specific target binding, conformational stability, scalable production, and an acceptable immunogenicity profile. Aim 1 focuses on improving existing and developing new mAbs based on 826827 and 864865. Computational development of 1000 mAb scaffolds per target epitope will be done using RFDiffusion, PyRosetta, and MPNN. Optimal mAbs will be selected based on production efficiency, competition with mAb826827, and blocking capability. Aim 2 focuses on developing new mAbs recognizing PvCSP VK210 and VK247. Computational approaches from Aim 1 will be applied to PvCSP, using blocking murine mAbs to guide the generation of new mAbs. Optimal mAbs will be selected based on production efficiency, competition with murine 2F2, and blocking capability. The project aims to establish which target proteins are functionally relevant for blocking Pv growth and determine the best therapeutic mAbs, either alone or in combination.

NIH Research Projects · FY 2026 · 2026-04

Project Summary: This proposal describes a five-year mentored plan for research training and career development that will facilitate the development of Dr. Devashis Mukherjee as an independent investigator in the pathogenesis of immunological effects of sepsis in preterm neonates. This plan will build on Dr. Mukherjee’s prior research training as a transcription factor biologist and his clinical experience as a neonatologist to investigate the role of myeloid-KLF2 in the pathogenesis of the dysregulated innate immune response responsible for the high mortality burden of preterm neonatal sepsis. Case Western Reserve University and Rainbow Babies and Children’s Hospital rank among the top pediatric institutions in the United States in terms of NIH funding, research output, and patient care excellence. In addition, Dr. Mukherjee will train under the mentorship of the Dr. Alex Huang and Dr. George Dubyak, who are renowned immunologists with a highly successful track record of mentorship. Gram-negative sepsis in a preterm neonate is highly fatal, with 1 in 2 of these babies dying despite timely initiation of antimicrobial treatment. Dr. Mukherjee has identified a critical transcription factor, Kruppel-like factor (KLF) -2, which decreases in the myeloid cells during gram-negative sepsis and elevates the immune system into pro- inflammatory overdrive through increased NLRP3 signaling and increased preponderance of aged, pro- inflammatory neutrophils in the circulation. Dr. Mukherjee will investigate the mechanistic basis of these findings through a combination of murine genetic models and human translational studies with two specific aims: Aim 1. Investigate how decreased KLF2 affects the neonatal neutrophil response to gram negative sepsis by increased NLRP3 signaling. Aim 2: Determine how decreased KLF2 at an earlier postnatal age leads to persistence of aged circulating neutrophils via cortical actin reorganization. These mechanistic studies will be critical in understanding the role of KLF2 in the dysregulated preterm immune response leading to the overwhelmingly high mortality in this vulnerable population. In addition, Dr. Mukherjee will gain significant training under the mentorship of Dr. Huang and Dr. Dubyak in neutrophil and inflammasome biology, advanced imaging techniques such as two-photon microscopy, advanced flow cytometry, and neutrophil functional assays. He will also receive training on murine models of bacterial sepsis under Dr. Jennifer Bermick at the University of Iowa, on chromatin immunoprecipitation and bioinformatic analysis under Dr. Berkley Gryder at CWRU, and on reporter assays to investigate transcription factor binding to promoter sites under Dr. Mukesh Jain at Brown University and Dr. Lalitha Nayak at Indiana University. This will lay the foundation for KLF2-targeted therapies as possible adjunctive treatments for sepsis in preterm neonates and Dr. Mukherjee’s transition to an independent investigator in developmental and myeloid cell biology.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract: In diseases ranging from Alzheimer’s Disease to Frontotemporal Lobar Degeneration to Primary Age-Related Tauopathy, tau misfolds and progressively accumulates. Yet, when and how the earliest misfolding events occur still remain unknown. Cellular mechanisms exacerbating and alleviating tau seeding are critical therapeutic targets that are also not well defined. The overall goals of this work are, 1) to identify the distribution and amount of tau seeds in a range of human brains—diseased, clinically normal, young, and old— and, 2) to identify cellular factors, including biochemical modifications, co-pathologies, and inflammatory cellular responses that modulate tau seeding. Using ultrasensitive real-time quaking-induced conversion (RT- QuIC) seed amplification assays we have developed for 3R/4R tau, 4R tau, 3R tau, and a-synuclein, we aim to define the age of onset, amount, geography, and biochemical diversity of tau seeds in human brain and also to delineate how tau seeds are influenced by co-pathologies. We build on our significant preliminary and published evidence that tau seeds are common in the human brain and arise frequently in cases with low levels of neuropathology and even in absence of disease. First, this study focuses on disease relevant structures of human misfolded tau, and utilizes multifaceted approaches including seed detection methods (including for mixed misfolded protein co-pathologies), biochemical assays, immunomapping, and structural profiling to evaluate the impact of post-translational modifications. Second, proteomic, snRNAseq, and spatial transcriptomic methodologies will establish cellular states existing in the brain microenvironment prior to and across the range of disease stages. Third, we aim to elucidate the relatively unexplored functions of myeloid and glial cells in tau seed propagation and clearance, building on evidence that inflammatory reactive oxygen species can modify tau seeds and potently alter their subsequent seeding abilities. The biologic ramifications of finding ubiquitous tau seeds throughout neurodegenerative diseases, and even occurring in young adults, remain unknown. By identifying the cellular microenvironments and states that exist at the earliest detectable stages of tau seeding, we aim to identify critical and therapeutically tractable targets to block tau seeding at the most clinicopathologically impactful stages.

NIH Research Projects · FY 2026 · 2026-03

Abstract Breast cancer (BCa) remains a leading cause of mortality among women globally, and current therapeutic paradigms often fail to prevent tumor recurrence and metastasis. Despite surgical resection being a cornerstone of treatment, residual tumor cells after surgery and the immune suppressive tumor microenvironment pose significant barriers to long-term survival and remission. Our research aims to address these unmet needs by leveraging combined theranostic efficacies of AKRO-6qc. The AKRO-6qc was designed for the highly specific binding followed by activation by cysteine proteases, which are highly overexpressed virtually in all human solid tumors. In this application we demonstrate that AKRO-6qc not only is useful as a targeted Fluorescence Image- Guided Surgery (FIGS) agent but also has significant Photothermal Therapy (PTT) characteristics that when combined, i.e. FIGS/PTT, synergize to eradicate BCa in mouse models of BCa. Using an immunocompetent syngeneic mouse model of BCa this innovative approach is designed to enhance the precision of tumor removal, induce a robust immune response, and prevent metastasis. Our plan is supported by three specific aims the first two aims optimizing use of AKRO-6qc for this approach and then culminating with Aim 3, which demonstrates utility. Aim 3.1 involves assessing the efficacy of AKRO-6qc-targeted FIGS/PTT in extending animal survival, delaying tumor recurrence, and preventing local and distant metastasis. Using the 4T1/luc transfected BCa cell line, we will perform tumor excision followed by PTT on female BALB/c mice. The study will measure the impact on primary tumor removal, survival, and distant metastasis. Aim 3.2 focuses on elucidating the relationship between AKRO-6qc-targeted FIGS/PTT and immune response. We will investigate the impact of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) on the immunologic response to FIGS/PTT. Strategies to enhance the immune response through depletion of MDSCs and co-administration of immune checkpoint inhibitors will be explored. We expect that FIGS/PTT will significantly reduce tumor recurrence and metastasis, leading to extended survival. By modulating the immune response, we aim to achieve a durable clinical response, potentially transforming the therapeutic landscape for BCa. Our comprehensive approach combining advanced imaging, targeted therapy, and immune modulation holds promise for overcoming the current limitations in BCa treatment and may ultimately improve outcomes for female patients with BCa and potentially for all patients with solid cancers.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract Epigenetic modifiers govern cell fate transition during animal development and their mutations drive multiple human congenital disorders; however, the molecular mechanisms underlying the roles of epigenetic modifiers in these normal and pathological processes remain poorly understood. It is widely believed that epigenetic modifiers function through the epigenetic marks they catalyze. Nevertheless, the discoveries of catalytic- independent role of epigenetic modifiers challenge this view, raising the question about the biological function of epigenetic marks. Mono-methylation of histone H3 at lysine 4 (H3K4me1) is a reliable mark of enhancers that shape cell identity, and its reconfiguration accompanies the differentiation of pluripotent stem cells, suggesting that the regulation of H3K4me1 plays an instructive role in cell fate transition. To examine this hypothesis, we investigated the catalytic function of LSD1 and LSD2, two paralogous histone demethylases targeting H3K4me1, in regulating gene expression during cell fate transition. Using state-of-the-art approaches such as precise genome engineering, epigenetic and transcriptomic profiling, and stem cell differentiation, we demonstrate functional synergism between the demethylase activity of LSD1 and LSD2 in regulating cellular differentiation. Based on these compelling preliminary data, here we propose to dissect the molecular mechanisms underlying how the demethylase activity of LSD1/2 regulates cell fate transition. The results generated from our proposed studies will not only reveal novel molecular mechanisms underlying the roles of H3K4me1 in gene regulation and cell fate transition, but also provide insights into understanding the pathogenesis of diseases driven by LSD1/2 loss-of-function. This research aligns with the NIH mission to advance our understanding of fundamental biological processes and contribute to knowledge relevant to developmental disorders and regenerative medicine.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in the United States and worldwide. People with HIV (PWH) with virus suppression on antiretroviral therapy (ART) have a 2-fold increased risk of developing CVD compared to people without HIV (PWoH), even when controlling for age and traditional CVD risk factors. One factor that may contribute to the increased CVD in PWH is cytomegalovirus (CMV) coinfection. Nearly all PWH and about half of all adults without HIV in the United States have CMV, which is independently linked to CVD. In preliminary spatial transcriptomic analyses of vascular tissues of PWH and PWoH, all of whom have peripheral artery disease, we find that the proportion of myeloid cells in regions of interest (ROIs) across arteries is significantly higher in tissues from PWH. CMV can reactivate from latently-infected monocytes as they differentiate into macrophages, and virological and immunological evidence suggests that PWH have more frequent CMV reactivation events than do PWoH, so the cardiopathogenic effects of CMV may be more pronounced among PWH due to the increased numbers of macrophages harboring replicating CMV. We hypothesize that CMV reactivation in infiltrating macrophages provides antigenic signals for CMV-reactive T cells in vascular tissues. We will use the following Specific Aims to test this hypothesis. Aim 1: To define the spatial context of CMV expression in vascular tissues of PWH and PWoH. In Aim 1, we will test this hypothesis by (1) defining the spatial context of CMV expression in situ in vascular tissues of PWH and PWoH with and without CVD, (2) quantifying CMV expression in macrophages in vessels from PWH and PWoH with and without CVD, and (3) confirming spatial relationships of CD4 and CD8 T cells and CMV-expressing target cells in the vasculature. Aim 2. To determine if serum-derived MDMs from PWH with CMV are more effective at activating and presenting CMV antigens to T cells than are MDMs from PWoH with CMV. In Aim 2, we will use in vitro experiments to determine if serum-derived MDMs from PWH with CMV, which preserves the influence of systemic inflammatory mediators, are more effective at activating autologous T cells than MDMs from PWoH with CMV. Then, we will determine if that activation is due to CMV antigen presentation by the serum-derived MDMs, and whether statin treatment of the MDMs, which inhibits CMV replication in vitro, directly impairs their T cell activating capacity. Our studies may define mechanisms whereby chronic viral infection drives T cell- mediated vascular pathology and may identify novel targets beyond traditional risk factors to prevent/treat CVD in PWH and PWoH. Furthermore, understanding the role of CMV in CVD, and whether its activity is susceptible to statins, will help inform the interpretation of the A5332/REPRIEVE (pitavastatin) and A5383/ELICIT (letermovir) trials in PWH.

NIH Research Projects · FY 2026 · 2026-02

Alzheimer disease (AD) is the fifth most frequent cause of death in the U.S. and currently affects nearly 55 million individuals of all ancestries worldwide; this number is predicted to double over the next 20 years. Clinical trials for effective therapeutics have almost all failed, and the few currently approved treatments provide only modest slowing of progression for a subset of individuals, with potentially severe side effects. Thus, focusing on additional and alternative therapeutic targets is critical to address this increasing health crisis. Genetically driven targets significantly improve the probability of successful clinical trials, but despite the identification of numerous AD-associated loci through GWAS, few have advanced to potential therapeutic intervention. In part, this is because GWAS itself is a blunt instrument that cannot differentiate among the many genes often underlying an associated locus. This leaves a critical gap where numerous GWAS-identified loci have not been sufficiently examined to support or refute their candidacy as a therapeutic target. ADAPTT aims to fill this knowledge gap by leveraging all available data from the growing datasets of the Alzheimer Disease Sequencing Project (ADSP) and the Alzheimer Disease Genetics Consortium (ADGC). Analyses of these genetic data will be significantly enhanced through integration of the currently separate SNV, indel, and structural variant (SV) data. We will also leverage extant in silico data and use existing and generate new in vitro molecular genetic functional data. Our goal is to identify the most likely functional genes/variations lying under each GWAS- identified locus, providing the foundation for critically needed, and genetically-driven, therapeutic development. We will achieve this goal through three parallel specific aims: Specific Aim 1 will integrate and analyze data for all SNVs, indels, and SVs within 54 AD GWAS-identified loci. We will leverage the increasingly multi-ancestry and diverse ADSP and ADGC datasets to reduce the list of probable functional genes/variations. Specific Aim 2 will assess the impact of these 54 loci on the clinically critical endophenotypes of age-at-onset and disease progression. We will first model disease progression and age-at-onset using harmonized data from the ADSP’s Phenotype Harmonization Consortium and then test the influence of the GWAS-identified loci on these endophenotypes. Specific Aim 3 will integrate extant and new molecular genetics functional data to validate causal genetic variations driving the locus associations. The results of this study will generate a set of genetically-driven potential targets that will accelerate the development of new and better therapeutics for AD.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT Periodontitis, caries, and halitosis are highly prevalent, have a large financial burden, and negatively impact quality of life. These conditions are each driven by the community of microbes in the mouth, especially oral pathogens. In contrast, during oral health, the oral microbiota is dominated by commensal, non-pathogenic species that are thought to modulate health, including through their interactions with pathogens. Select oral microbes are well characterized in the lab, but the behavior of these organisms in the human oral cavity is not well described. Over the last decade, researchers have used RNA sequencing directly from the human oral cavity (metatranscriptomics) to define the overall bacterial behavior in subgingival plaque, in supragingival plaque, and on the tongue. These studies were instrumental in uncovering broad changes in bacterial gene expression between health and diseased states. However, there remains a lack of understanding of the behavior of individual taxa in the human oral cavity. We recently started to address this gap in knowledge by characterizing the gene expression of the pathogen Porphyromonas gingivalis during periodontitis in 93 human metatranscriptomes. This proposal expands on our approach by leveraging 697 publicly-available human oral metatranscriptomes to identify the gene expression of key oral pathogens, pathobionts, and commensals across oral sites and disease states. This study will be supported by pangenomic approaches to capture the gene expression of diverse genotypes and an in silico validation approach to ensure high specificity and sensitivity. Our findings will uncover the biology of each microbe during oral health and disease, including virulence factor expression, metabolic processes, and other host-microbe and microbe-microbe interactions. Also, we will examine the variation in behavior for each taxon of interest across hosts, oral sites, and disease states. Finally, these analyses will help researchers identify key genes to study based on the expression levels in the human oral cavity. To this end, we will share our data using interactive interfaces in the Human Oral Microbiome Database, an expertly-curated and highly-used resource for oral microbiologists. In sum, this project will be instrumental in describing the gene expression of oral microbes in the human oral cavity, uncovering new biology of these important bacteria, and empowering researchers to study genes relevant to human health and disease.

NSF Awards · FY 2026 · 2026-02

Transferring data between memory and processing units in conventional computing systems is expensive in terms of energy and latency. This data movement consumes significant energy and slows down the processing speed, particularly for data-driven applications such as machine learning workloads. In-memory computing (IMC) is a promising solution to address this issue by performing computations inside memory. However, IMC techniques using emerging memory technologies suffer from multiple key technical challenges that limit their applicability in today’s computing systems. Significant error in the computations is likely with these IMC techniques. The processing latency also increases significantly with data-width; e.g., this is approximately an exponential increase for the multiplication operation. This project addresses the critical challenges with today’s IMC techniques by exploiting a simple and uniform representation of data. Complex arithmetic operations on weighted binary data are transformed into simple bit-wise memory-friendly operations on uniform bit-streams. Successful completion of the project will accelerate and reduce the power and energy consumption of a wide range of applications from biomedicine (e.g., retinal implants), to security (e.g., miniaturized unmanned aerial vehicles), to smart sensors and machine learning (e.g., speech recognition). The team will share the project outcomes, including articles, simulators, and hardware and software toolkits, with the research community. The findings and technical outputs will be integrated into instructional materials for graduate, undergraduate, and K-12 classroom settings. The project activities will engage active participation of graduate and undergraduate students. This project combines the complementary properties of two emerging technologies, IMC and unary computing (UC), to implement a high-performance, reliable, and energy-efficient data processing platform with high computational ability. The presented platform addresses the technical challenges of the IMC techniques using emerging memory technologies. It also addresses the latency and cost-efficiency of the existing UC designs with combinational CMOS logic. The technology explored in this project aims to improve the robustness of IMC operations to noise and variation by processing uniform bit-streams. The platform is highly parallel and effectively scales with the size of computations. It enables fast, accurate, and simple execution of a wide range of arithmetic operations entirely in memory. It enjoys independent bit-wise operations, avoiding long chains of operations, an important source of in-efficiency in today’s IMC techniques. The target platform is general and can be used for various applications. This project is jointly funded by the Software and Hardware Foundations (SHF) program in the Computing and Communication Foundations (CCF) division, and the Established Program to Stimulate Competitive Research (EPSCoR). 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 · 2026-02

Women comprise about 50% of the 36.7 million people living with HIV worldwide and in many sub-Saharan African countries including Nigeria, ~2 out of 3 HIV infected adults are women. Even more worrisome is the observation that overwhelming number of new infections in Nigeria occur among young women of childbearing age, and as such, one-third of all global cases of mother-to-child transmission of HIV occurs in the country. Not only is the burden of HIV higher in women, the impact of its scourge is far more reaching. HIV is the leading cause of morbidity and mortality among women of reproductive age in Nigeria. HIV complicates every aspect of health across a woman’s lifespan, including reproductive health where it impacts partner sero-sorting and sexual habits, fertility desires and contraceptive choices, pregnancy and delivery, menopause and aging. Tackling the myriads of health challenges confronting women living with HIV is a necessary step to achieving the WHO global strategy for women’s, children’s and adolescent health. It will require nurturing a critical mass of local health scientists and equipping them with the skills to conduct valid research that addresses the local health needs of women living with HIV. To address these needs, we established the Emory-Nigeria HIV Research Training Program (EN-RTP). The EN-RTP leverages the research education infrastructure at Emory University and the partnering Nigerian institutions (Nigerian Institute of Medical Research (NIMR); University of Lagos (UNILAG); and AIDS Prevention Initiative Nigeria (APIN)) to provide state-of-the-art in-country research training with focus on methodologies, rigorous mentorship, and grant management capacity building. The EN-RTP training is focused on three main domains of HIV/women’s health research: a) HIV prevention and reproductive health; b) Challenges in HIV therapeutics unique to women living with HIV (WLWH); and c) Complications of chronic HIV infection relevant to WLWH. Preceptors are selected based on their expertise in these areas and their international research education and mentoring experience. We can report that the EN- RTP is now an established program with a cohesive administrative structure and program plan that includes both didactic and mentored research components implemented by a multidisciplinary team of in-country faculty and US-based investigators who have a wide range of mentoring experiences. The short- and medium-term accomplishments include high scholar productivity (over $3M in grant funding, including 3 NIH K 43 awards and more than 150 peer-reviewed publications by trainees), fostering robust scientific networking opportunities, developing emerging in-country scientific leaders, and nurturing the next generation of HIV research mentors. The EN-RTP has demonstrated a potential to be truly transformative in promoting mentored research training and the growth of the HIV biomedical research workforce. Committed to the primary goal of capacity building in HIV research, we look forward with enthusiasm the next cycle – particularly the opportunity to pilot new initiatives and best practices arising from our evaluation processes to enhance program outcomes.

NIH Research Projects · FY 2026 · 2026-01

Project Summary Mitochondrial dysfunction is an early event in neurodegenerative diseases including Alzheimer's disease (AD) and Frontotemporal lobar degeneration with tau pathology (FTLD-Tau). Tauopathy is defined by abnormal Tau protein aggregation and hyperphosphorylation, which results in the formation of neurofibrillary tangles within neurons in AD and FTLD-Tau. CHCHD10 plays a crucial role in regulating diverse mitochondrial functions, such as respiration, genome stability, dynamics, cristae organization, and oxidative phosphorylation. In our preliminary study, CHCHD10 was found to be downregulated in the brains of AD, FTLD-Tau, AD-derived neurons, and P301S-Tau mice. Furthermore, either depletion or the presence of CHCHD10-Q95* increases tau seeding activity and tau aggregation in vitro cell lines. Increasing CHCHD10 significantly reduced tau pathology in P301S- Tau mouse brains, human AD fibroblast-converted neurons, and in vitro cell lines. As a result, this study has two major goals: (1) to validate and extend CHCHD10's role in these phenotypes in vivo and ex vivo, and (2) to investigate potential mechanisms by identifying proteomics and transcriptomics signatures in CHCHD10- transduced human neurons derived from AD patients and assess the post-translational modifications on human tau altered by CHCHD10 in PS19 mouse brain. The successful completion of this proposal will: (1) provide insights into CHCHD10-associated mechanisms in tauopathy in AD; and (2) facilitate the therapeutic potential of increasing CHCHD10 in tauopathy in AD.

NIH Research Projects · FY 2025 · 2026-01

PROJECT SUMMARY/ABSTRACT Prior research has documented that social determinants of health such as neighborhood disadvantage and school context are associated with youth mental health3,7,10,11, with neighborhood effects on youth outcomes being mediated by parenting factors4. However, research on the role of these contextual factors in the trajectories of parenting and youth mental health and their relationships has been limited. Additionally, this prior work shows the importance of targeting parenting in family-focused preventive interventions in geographical areas with high contextual risk. While neighborhood economic disadvantage and subjective perceptions of neighborhood are associated with outcomes of preventive interventions32, 34, this prior work has used limited objective measures of social determinants of health, has had inconsistent longitudinal follow-up, focused on limited outcomes, and did not consider how social determinants of health influence intervention engagement. The proposed research will address these limitations with several aims: (1) Determine how neighborhood and educational risk and protective factors are related to youth mental health trajectories across childhood and adolescence and the role of parenting as a mediator between context and youth mental health trajectories, (2) Investigate whether neighborhood and educational risk and protective factors are associated with engagement in and response to the Family Check-Up, a family-focused preventive intervention, and (3) Determine whether findings from the first two aims differ based on urbanicity, race, or ethnicity. The results have implications for clinical practice and research in the development and dissemination of family-focused preventive interventions that promote positive family relationships and youth mental health for all families. The work addresses the NIMH Strategic Plan by aiming to examine trajectories of mental illness, strive for prevention, and advance services to strengthen public health. The proposed research and training plan, which will occur in a supportive, collegiate environment at Case Western Reserve University, will provide the researcher with critical training to support the transition to becoming an independent researcher in developmental psychopathology and prevention science. Specific training goals include (1) Develop a focused understanding of how neighborhood and educational social determinants of health influence parenting and youth mental health, focusing on how this perspective can inform development and dissemination of preventive interventions, (2) gain expertise in leveraging geocoded data to answer questions related to social determinants of health, family functioning, and intervention outcomes, and (3) master the use of complex quantitative methods to analyze longitudinal data. The applicant has assembled a mentorship team with an expertise in the areas which she plans to gain additional experience, and this team will provide superior guidance that will support her increasing independence as a researcher.