University Of Pennsylvania

NIH Research Projects · FY 2026 · 2026-04

Project Summary: The SPARC Portal provides a community hub for rapidly developing and highly integrative fields such as neuromodulation, interoception, and gut-brain interactions. It combines repository services with a web application that fosters community and data integration. The SPARC infrastructure was initially funded through a significant 8-year investment by the NIH Office of the Director to serve as the data integration, analysis, mapping, and publishing platform for the NIH Stimulating Peripheral Activity to Relieve Conditions (SPARC) program, focused mainly on the autonomic nervous system (ANS). The SPARC Portal transitioned to an open repository in 2023 with an expanded scope beyond the ANS to support the new NIH data-sharing policy. With its unique focus on the PNS and systems physiology, the SPARC Portal provides a critical neuroscience-focused resource that complements the investments by the US BRAIN initiative in data-modality-specific data archives established by the BRAIN Initiative. Our central hypothesis is that developing and maintaining a FAIR, open- science data repository ecosystem to support science bridging the body and brain will significantly advance scientific understanding, serve life science applications, and substantially impact clinical medicine. Currently, the repository hosts over 300 high-impact, large-scale datasets contributed by over 600 investigators. It supports integrated multi-modal datasets of high-resolution imaging, time series, -omics, computational models, anatomical maps, and other data modalities. It provides seamless access, search, and interaction with these datasets through a dedicated web application. The SPARC Data Resource Center manages the resource. It has been actively involved in developing standards, best practices, and outreach to establish a larger community around the data submitted to the repository. Over 5000 investigators subscribe to the quarterly SPARC newsletter for updates on relevant events, new datasets, and community insight articles. In this proposal, our goals are (1) to continue to provide sustainable data and tool publishing services to the larger scientific community, focusing on datasets bridging the body and brain. (2) to maintain and sustain the infrastructure and governance of the resource, ensuring that the platform remains viable long-term and has transparent governance processes, and (3) continue to foster and expand the SPARC community as we firmly believe that the success of a repository extends beyond the data that is made public through the repository and instead requires fostering a community around the resource and the data. The proposed project facilitates the continuation and expansion of the SPARC portal as a sustainable, interoperable data repository for the scientific community.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY The prevalence of Alzheimer’s disease (AD) and related dementias (ADRD) in the United States is on the order of seven million and likely to grow over the next two decades. The molecular hallmarks of ADRD are misfolded proteins (b-amyloid and tau), and although anti-amyloid antibody drugs have recently been approved for AD treatment, they have limited effectiveness, are often associated with significant side effects, and amyloid depo- sition correlates only moderately with cognitive status. This situation has spurred the search for additional mech- anisms underlying the disease. Glucose is the main substrate for ATP synthesis in the brain. A well-known feature of ADRD is disruption of the brain’s energy metabolism, which has been linked to defective processing of, or reduced access to, glucose resulting in brain hypometabolism. It is also known that ketones (b-hydroxy- butyrate and acetoacetate) formed in the liver from medium-chain length fatty acids can act as an alternate fuel for oxidative phosphorylation. Non-invasive assessment of the cerebral metabolic rate of oxygen (CMRO2) glob- ally and regionally would allow the age and neurodegeneration related brain energy gap to be quantified and validate ketogenic intervention by quantitative brain imaging. Currently, positron emission tomography (PET)- based brain oximetry relying on oxygen-15 tracers is considered the “gold-standard” imaging method for mapping cerebral energy O2 metabolism. But 15O PET is complex, costly, and not widely available. Over the past decade magnetic resonance imaging (MRI) methods have emerged for measuring CMRO2 noninvasively. Both PET and MRI derive CMRO2 from measures of venous and arterial O2 saturation to estimate oxygen extraction fraction (OEF) and, along with cerebral blood flow (CBF), CMRO2. The proposed research builds on recent developments in the applicants’ lab for 3D CMRO2 mapping via a new constrained qBOLD technique based on an extension of the Yablonskiy model for signal decay due to partially deoxygenated hemoglobin in the capillary network, in combination with quantitative susceptibility mapping. We propose to first enhance the method in terms of image acquisition efficiency and to examine its sensitivity to detect regional variations in OEF, CBF, and CMRO2 both at baseline and in response to physiologic stimuli in test subjects. Subsequently, we will investigate the growing energy gap with age and, more so, in ADRD, and evaluate the hypothesis in a small group of AD patients that ingestion of a ketone ester drink in the form of triacyl triglycerides of C-8 saturated fatty acids induces a transient increase in O2 metabolism and, possibly, acute improvement of cognition. This new MRI-based imaging tech- nology for brain oximetry can readily be integrated into standard brain imaging protocols to provide means for evaluation of the metabolic consequences of ADRD at baseline and in response to intervention.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Heart failure is a major cause of morbidity and mortality, with orthotopic heart transplant (OHT) considered the gold standard treatment for those eligible. As a result of improving mechanical circulatory support (MCS) technology, in 2018 the national heart allocation policy changed to prioritize candidates requiring temporary MCS (tMCS) (e.g., extracorporeal membrane oxygenation, intra-aortic balloon pump). This change resulted in a significant increase in tMCS use prior to OHT nationally. Throughout this period, infection remained a major cause of morbidity and mortality post-transplant, with bloodstream infections (BSI) being a particularly serious complication. In non-transplant patients, tMCS is associated with BSI, although no studies have specifically addressed this in the transplant population, which is unique due to need for high dose immunosuppression and different indications for tMCS use. To prevent BSI, we must understand the mechanisms by which tMCS contributes to BSI, which we hypothesize is due to changes in the gut and skin microbiome of OHT recipients. This occurs through the tMCS device disrupting skin integrity to alter the skin microbiome as well as tMCS altering gut perfusion, with related gut microbiome changes and translocation of dominant gut bacterial species. Additionally, BSI may impact post-OHT outcomes of graft function and mortality via infection and immune response as well as indirectly in changes to immunosuppression, which requires further exploration. In this study, we plan to address these knowledge gaps by studying a large retrospective and prospective cohort of OHT recipients. Specifically, we plan to determine the risk factors for post-transplant BSI in OHT recipients, with a focus on tMCS (AIM 1); define the impact of tMCS pre-transplant on the skin and gut microbiome of OHT recipients (AIM 2); and determine the association between early BSI and post-transplant outcomes of rejection, graft failure, and death (AIM 3). For Aims 1 and 3 we will collect retrospective data from a large cohort of OHT recipients, utilizing advanced statistical methods including time varying covariates and propensity matching to address the heterogeneity inherent in this population. Aim 2 will be accomplished through prospective pre- and post-transplant collection of biospecimens for microbiome analysis to evaluate changes and impact on infection. The results of this study will lead to paradigm shifts in how we think about tMCS before OHT and treat recipients after OHT to prevent infection, which may enhance organ allocation practices moving forward. The aims are combined with a robust training plan that includes formal education in biostatistics and epidemiology as well as microbiome analysis, formal benchmarks for progress including presentation at seminars and international conferences, and extensive research experience under the guidance of an expert mentoring and advisory team. This proposal will form a strong foundation for my continued development toward a career as an independent investigator with a research program focused on improving outcomes in OHT recipients.

NIH Research Projects · FY 2026 · 2026-04

Myocardial fibrosis (MF) has been traditionally considered the critical anatomic substrate for cardiac dysfunction, remodeling, and malignant arrhythmia. During my postdoctoral training, supervised by Dr. Saman Nazarian, I adopted a multimodal strategy to characterize myocardial lipomatous metaplasia (LM) from cardiac CT images and scar from cardiac MRI images. We discovered that myocardial LM is prevalent in ischemic and non-ischemic cardiomyopathy, exhibiting distinct electrical features from MF and playing a more crucial role in cardiac electrophysiological remodeling. This challenges the conventional understanding of pathologic cardiac architecture and suggests new therapeutic targets. The proposed work builds on my ongoing postdoctoral research to investigate myocardial LM using data from the Penn Medicine Biobank (PMBB), which includes 23,940 participants (by 2024) with genotypes and cardiac CT images. We have developed and validated a deep-learning model that accurately segments myocardial LM from CT images. We will apply this model to PMBB CT images to achieve the following aims: Aim 1: Establish the phenotypic profile of LM across etiologies of cardiomyopathy and assess its association with outcomes. o Specific Aim 1a: To define the prevalence, distribution, volume, and patterns of LM stratified by underlying cardiomyopathy PMBB (K99 stage). This aim will mitigate current hurdles in recognizing cardiomyopathy etiologies, allowing for earlier disease-specific interventions. o Specific Aim 1b. Assess the association of LM and composite outcome, including heart failure, ventricular tachycardia, stroke, or all-cause mortality in PMBB (R00 Stage). This aim will enhance risk stratification of cardiomyopathy patients, enabling early prophylactic or therapeutic strategies. Aim 2: Characterize the genetic architecture of LM and estimate its association with that of cardiac adiposity and myocardial fibrosis. o Specific Aim 2a: Assess the heritable basis of LM and its relationship to cardiometabolic traits. (K99 Stage). This may lead to mechanistic and translational studies of LM focused on precision medicine. o Specific Aim 2b: Estimate the contribution of cardiac adiposity and myocardial fibrosis to LM formation using a Mendelian randomization (MR) framework (R00 Stage). This aim could aid in identifying candidate therapeutic targets for preventing LM formation or alleviating LM burden in patients with cardiomyopathy. In conclusion, this study will unravel the biological and genetic mechanisms that underly myocardial LM, recently recognized as the most potent determinant of cardiac dysfunction and malignant arrhythmia. Project Summary

NIH Research Projects · FY 2026 · 2026-04

While some patients with previously untreatable blood cancers have achieved long-term remissions following CAR T cell therapy, others relapse after months to years. While engraftment and expansion are well characterized clinical surrogates of a durable anti-tumor effect, the attributes and origin of CAR T cells with prolonged function remain unknown. Prior research on CAR T cell-intrinsic properties in the treatment of hematologic malignancies has primarily focused on the manufactured product, but did not capture or define the T cell clones that are directly responsible for functional persistence and durable remissions. We have now found that long-lived CAR T cells up to 5 years post-infusion have a distinct CD4- CD8a- “double-negative” (DN) TCRαβ+ effector memory T cell phenotype. Our multimodal single-cell analyses have revealed that (i) the clones that eradicate leukemia in the initial phase differ from those that perform long term immunosurveillance, and that (ii) long lived DN CAR T cells show specific transcriptional signatures, with remarkable similarity to persistent CAR T cells in small cohort of children with B-ALL, to rare TCRαβ+ DN T cells from healthy donors, and to melanoma patients responding to dual checkpoint blockade. The CD4 and CD8 glycoproteins are co- receptors in TCR recognition of class II or class I major histocompatibility (MHC) – peptide complexes, respectively, serving to stabilize the TCR:peptide/MHC. Since DN T cells accumulate in chronic inflammatory diseases, these observations raise the intriguing possibility that in some settings, chronic antigen exposure can lead to a unique and previously under-appreciated T cell differentiation trajectory that is distinct from that found in “classic” CD8 T cell exhaustion. This dual PI proposal unites experts in immune cell therapies and evolutionary biology to test the overarching hypothesis that the fittest CAR T cells adopt a DN phenotype to withstand the demands of long-term immunosurveillance. In Aim 1 we will define the contribution of DN T cells to the long-lived CAR T cell population in patients with hematologic malignancies using flow cytometry and single cell multiomic analyses of CAR T cells persisting >12 months after infusion in patients with CLL, NHL, and MM. By leveraging our extensive cryorepository and well-annotated clinical trial outcome data we will be able to correlate CAR T cell phenotype to their functional persistence. In Aim 2 we will identify the cellular origin and evolutionary paths of long-lived CAR T cells. To distinguish the possibilities that persistent CAR T cells originated as true DN T cells vs. conventional T cells that downregulate the CD4 or CD8 co-receptors, we will use complementary approaches to trace DN persistent clonotypes back to their infusion origin. In Aim 3 we will determine whether and how DN T cells resist exhaustion during chronic stimulation, using a novel high-fidelity T cell exhaustion model along with gain- and loss-of function interventions to illuminate this biology. Together, these studies will illuminate the lineage relationships of various endogenous and engineered T cells and guide the development of more effective CAR T cell therapies.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY My research program over the next five years is focused on the regulation and functions of RNA editing and sensing to advance our understanding of RNA-mediated immune regulation, a relatively new field with emerging roles in human immune diseases. ADAR1-mediated Adenosine-to-Inosine (A-to-I) RNA editing is one the most abundant RNA modifications/edits found in humans. The key function of ADAR1 editing is to label endogenous double-stranded RNAs (dsRNAs) as “self” to evade unwanted recognition by dsRNA sensor MDA5 as “non-self”. Loss of ADAR1 editing leads to accumulation of unedited dsRNAs in the cells, which eventually activate MDA5-mediated interferon (IFN) immune response. This unwanted “self-sensing” of endogenous dsRNAs causes rare autoimmune diseases in humans and embryonic lethality in mice. My recent research revealed that insufficient RNA editing can be caused by common genetic variants located in or nearby the dsRNAs, even in the presence of fully functional ADAR1. Surprisingly, a large number of these genetic variants were also found as risk variants in multiple human immune diseases. My analysis showed that, these risk variants collectively reduce RNA editing levels of immunogenic dsRNAs to increase cellular “dsRNA burden” in disease samples, which was coupled with elevated IFN immune responses, presumably through activating MDA5-mediated RNA sensing. While my research uncovered a previously unknown function of RNA editing and sensing in common immune diseases, it remains unclear how RNA editing neutralizes the immunogenicity of various endogenous dsRNA species and how erroneous RNA sensing leads to inflammation and immune diseases. Built on my previous findings, we aim to address these questions by developing new tools to uncover the regulatory mechanisms underlying RNA editing and sensing. On one hand, we have been developing tiling base- editor screens to identify functional protein domains and residues of ADAR1. Using changes in RNA editing and cellular immune responses as the functional readout, we aim to uncover essential functional domains of ADAR1 with their associated endogenous dsRNA species and downstream dsRNA sensors. This functional genomics approach will not only help dissect the multifaceted roles of ADAR1 in immune regulation, but also uncover new functions of ADAR1, hidden immunogenic dsRNA species, and previous unknown dsRNA sensors. On the other hand, we are actively developing novel imaging and sequencing methods to specifically detect RNA sensing activities in cells and tissues. We will utilize post-translational modifications (PTMs) and/or protein- protein interactions unique to the activation of each RNA sensors to guide our assay design, so that we can distinguish between different RNA sensing pathways while still capture any potential synergistic effects. In the long-term, we aim to apply our methods to patient-derived tissues, hoping to uncover the incorrectly activated RNA sensing pathways in patients and the relevant cell types that together contribute to immune diseases. By integrating functional genomics, transcriptomic analysis, and immune profiling, this program aims to bridge the gap of knowledge in RNA editing and sensing. While we focus on elucidating the fundamental mechanisms regulating RNA-mediated immune regulation, our findings will also pave the route for developing novel therapies targeting at RNA editing and sensing pathways to treat cancer and immune disease.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract: Inflammatory bowel disease (IBD) is a chronic inflammatory process initiated in the intestinal mucosa, typically onset in young adults. IBD causes severe morbidity and emergent complications often necessitating surgery, with a high proportion of IBD patients relapsing or being unresponsive to anti-TNF therapy. Despite the urgent clinical need for improved IBD treatments, pathophysiology of IBD remains incompletely understood, thought to result from complex genetic and environmental factors. Abnormalities in adaptive and innate immunity, cellular and ER stress, increased mucosal barrier permeability, dysbiosis, and genetic variants in autophagy and immune signaling components may contribute to increasingly pro-inflammatory gut immune dynamics, ultimately spreading to extra-intestinal manifestations in almost half of patients. Adaptive immunity, especially the Th17 T-cell subset converting to a pro-inflammatory phenotype, has been widely accepted as an important proponent of inflammation in IBD, with specific microbial strains and viral integration implicated as possible drivers. However, the antigen presentation landscape of T-cell epitopes has never been systematically characterized. In this research effort, we will profile antigen presentation by experimental immunopeptidomics, then computationally prioritize these HLA-presented peptides for immunogenicity, also examining molecular mimicry with self-antigens, to more deeply understand IBD pathophysiology (Aim 1). Adaptive immune responses can be triggered by ER stress, a biochemically complex phenomenon whose far-reaching role in IBD contributes to numerous pathologic features. Since evidence shows ER stress alters antigen presentation, we will attempt to draw a mechanistic link in the context of IBD, resolving specific antigen presentation changes induced by ER stress (Aim 2). Finally, we will attempt to validate immunogenicity of peptide epitopes by detecting antigen-specific T-cell receptors. Combining the abundant IBD resources in our biobanks and IBD Center with the expertise of an experienced, interdisciplinary team, we will endeavor to answer these important questions about adaptive immunity in IBD, while creating a high-quality dataset that lays the groundwork for future studies.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY: Parental experiences such as diet and stress can affect the phenotype of subsequent generations through non-genetic inheritance. This process, where phenotypic changes are passed on without altering the DNA sequence, can alter phenotypes of the F1 generation of mice or even beyond. While epigenetic inheritance to the F1 generation is well-established in mammals, beyond the F1 generation to the F2 generation and further has only been demonstrated in organisms, like C. elegans and plants. The mechanisms behind epigenetic inheritance beyond the F1 generation in mammals are still poorly understood due to a lack of robust and easily quantifiable phenotypes. Our labs have recently uncovered that T cells can epigenetically alter phenotypes across generations. T cell-deficient male mice and their F1 and F2 offspring generated by crossing to WT mice exhibited defective sebum secretion. Mice lacking CD4-/CD8- double negative (DN) T cells were also found to have defective sebum secretion. These discoveries provided a novel model to study how T cells, including DN T cells, can epigenetically alter progeny phenotype. It is hypothesized that the epididymis, a long, convoluted tubule in the male reproductive tract, secretes extracellular vesicles filled with small regulatory RNA (sRNA) to alter sperm sRNA expression that can transfer epigenetic information to the next generation zygote. We have observed that T cell- deficient mice had dysregulated small regulatory RNA (sRNA) and gene expression in both sperm and the epididymis, suggesting that T cells may interact with the epididymis to alter these processes. We hypothesize that T cell activity (specifically DN T cells) alters the gene and sRNA expression of the epididymis and sperm, resulting in the transfer of sebum secretion phenotypes to succeeding generations of progeny. Our research aims to address the following. (Aim 1) We will characterize the expression landscape and function of epididymal DN T (eDNT) cells by analyzing (1) immmunophenotype through flow cytometry and transcriptional profile through single cell RNAseq, as well as (2) DN T cell-derived immunoregulatory cytokines effects on epididymis gene and sRNA expression. (Aim2) Second, we will determine how eDNT cells affect the (1) sperm sRNA expression and epididymis gene and sRNA expression, (2) the inheritance pattern of epigenetically heritable defective sebum secretion, and (3) epigenetic inheritance of sebum secretion. This work aims to probe potential mechanisms that drive epigenetic inheritance, linking the parental immune state to phenotypic alterations in future generations through the activities of eDNT cells. To work towards my career goal to become a principal investigator, I have outlined a training plan at the University of Pennsylvania, focusing on experimental design, scientific communication, research collaboration, and mentorship skills. The resources at Penn offer an ideal environment for my growth as an immunologist and epigeneticist, providing the opportunity to integrate research in immunology and epigenetics.

NIH Research Projects · FY 2026 · 2026-04

SUMMARY For many non-integrating RNA viruses, a typical course of infection involves a brief period of peak viral burden followed by rapid resolution. However, the virus or viral products are detected in a subset of individuals for a prolonged period for a growing list of viruses previously considered non-persistent. Prolonged infection may contribute to long-term complications and increased opportunities for transmission. In preliminary data, we developed an animal model of persistent murine astrovirus (MuAstV) infection that we propose to apply towards elucidating how the environment determines the duration of enteric infection. Astroviruses are RNA viruses that are a common cause of self-limiting gastroenteritis in humans following fecal-oral transmission, although like other gut viruses, some individuals display prolonged shedding for unknown reasons. We found that routine cage change procedures induce a stress response characterized by a spike and drop in glucocorticoid levels that leads to rapid clearance of MuAstV infection in mice. In contrast, the virus establishes a robust persistent infection if the mice remain in the same cage for the duration of the experiment. We will first determine how MuAstV establishes a persistent infection in the unperturbed setting, focusing on immune evasion mechanisms of the virus including how goblet cells potentially represent an immune-privileged niche. Then, we will determine how the cage change procedure mediates clearance of MuAstV, especially the role of the glucocorticoid-CD8 T cell axis representing a novel contribution of the stress response to viral dynamics. Cage change routines are an important variable in animal research that are often ignored. Moreover, stress and glucocorticoids are pervasive aspects of human biology. We anticipate identifying fundamental mechanisms involved in how the immune system reacts to stressful environmental perturbations to regulate the duration of viral infections in the gut. This information may inform intervention strategies that can be deployed to diminish the duration of viral infection and window of transmission.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Autophagy, a conserved catabolic process mediated by autophagy-related (ATG) proteins, is integral for maintaining cellular homeostasis. Recent studies suggest that ATG proteins are also necessary for immune responses through processes that are mechanistically distinct from autophagy. The Cadwell lab has identified a novel innate immune mechanism whereby cells produce extracellular vesicles of endosomal origin (exosomes) which can neutralize bacterial toxins and inhibit viral pathogens in the lung and bloodstream. The production of these extracellular vesicles, termed “defensosomes”, is induced by innate immune sensors such as Toll-like receptor 9 (TLR9) and dependent on the ATG protein ATG16L1. However, the molecular pathways governing defensosome biogenesis and release remain elusive. This study aims to elucidate these mechanisms, focusing on the roles of ATG16L1 and its binding partner TMEM59 in defensosome biogenesis, as well as how TLR9 signaling modulates RAB7 activity for defensosome release. We will use a tractable lung epithelial cell culture system and measure defensosomes released in the blood stream of mice as an in vivo readout. Aim 1 investigates how the interaction between ATG16L1 and TMEM59 promotes defensosome biogenesis. We hypothesize that ATG16L1 and TMEM59 facilitate the formation of intraluminal vesicles within multivesicular endosomes. Aim 2 examines how TLR9 signaling influences RAB7 activity to incite defensosome release. We propose that TLR9 activation leads to the upregulation of a GTPase-activating protein, promoting RAB7 dissociation from MVEs, thus diverting defensosome precursors to the plasma membrane for release. This research will provide critical insights into the molecular mechanisms of defensosome biogenesis and release, while also enhancing the understanding of the intersection between autophagy and innate immunity, additionally contributing to the broader field of extracellular vesicle biology.

NIH Research Projects · FY 2026 · 2026-04

Abstract A few hundred genes in mammals are regulated by genomic imprinting. These genes are epigenetically marked and exhibit parental-of-origin-specific gene expression. Imprinting plays a role in the transmission of a number of human disorders, including Beckwith-Wiedemann Syndrome and Silver-Russell Syndrome, where the sex of the parent transmitting the affected gene(s) determines whether offspring will be impacted. Additionally, imprinted genes are primarily responsible for the block to uniparental development, highlighting the importance of precise dosage and function of these genes during development. Our work aims to elucidate the mechanism(s) by which parental identity of imprinted genes is established, maintained and reprogrammed in the germline. In-depth study of imprinted genes will further inform our understanding of genome regulation and nuclear architecture, as imprinted genes are located in large domains and are often regulated by long non- coding RNAs, CTCF-dependent insulators, and allele-specific epigenetic modifications. We will focus on the H19/Igf2 and Grb10/Ddc1a imprinted domains, both of which harbor CTCF-binding imprinting control regions (ICRs) that regulate imprinting. H19/Igf2 and Grb10/Ddc1a also represent imprinted clusters with DNA methylation at ICRs conferred in the male and female germline, respectively. Using genetically modified mice and cell lines, we aim to discover the mechanism(s) for germline establishment of DNA methylation at ICRs and its subsequent maintenance after fertilization when the majority of the genome is reprogrammed. This work will also contribute to a better understanding of critical species-specific sequences and epigenetic machinery involved in these processes. Additionally, we will investigate the mechanism of TET1-mediated active DNA demethylation during germline reprogramming for imprints and other sequences. We recently developed TET1 catalytic variant mutants to dissect the requirement for non-catalytic activity and iterative oxidation of 5-methylcytosine by TET enzymes in vivo. Using these newly derived variants, we will elucidate TET1-dependency of ICRs and other sequences in the female germline. Additionally, we intend to identify TET1-interacting proteins in the germline to illuminate further the role of active DNA demethylation during germline reprogramming. Finally, we will investigate how male and female gametes with methylation defects due to Tet1 mutation led to mid-gestation lethality. Together, our work will deepen our understanding of epigenetic regulation and reprogramming during mammalian development.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death worldwide and the fastest rising cause of cancer-related death in the US. The majority of patients with HCC present with unresectable disease at diagnosis and a life expectancy of less than 20 months. This dismal prognosis has motivated the development of an expanding repertoire of treatment regimens, including locoregional therapies (LRT) such as transarterial chemoembolization (TACE) and radioembolization, as well as systemic therapies, notably tyrosine kinase inhibitors and immune checkpoint inhibitors, both alone and in combination. Despite these advances, treatment responses remain variable with most patients progressing on standard-of-care therapies. This deficiency issues, in large part, from limitations of current preclinical models in (i) recapitulating the intertumoral heterogeneity that characterizes HCC and (ii) predicting patient response to therapeutics. While patient-derived tumor models have been demonstrated to more faithfully recapitulate the heterogeneity of human tumors, there has been limited validation of the translational relevance of these models with respect to their ability to provide translationally reliable information for the design, testing and/or outcome evaluation of novel or existing therapies. Indeed, the creation of new patient-derived models of HCC requires rigorous validation of the resulting tumors to confirm their fidelity to the cancer of interest and robust credentialing criteria to ascertain their biological relevance and reliability as surrogates of patient response. In preliminary studies we have: 1) generated orthotopic HCC PDXs (PDOX) in rats derived from patients with unresectable HCC, 2) curated a clinical database of these patients including clinical and histologic phenotypes and treatment course 3) demonstrated the ability to perform LRT in these rat HCC PDOXs 4) generated humanized immune systems (HIS) and humanized livers (HL) in immunocompromised rats. The proposed project will build on this work to establish and validate a novel rat HCC PDOX model that incorporates the features required to realize the potential of the growing armamentarium of treatment paradigms for patients with HCC. We hypothesize that patient-derived rat models of HCC incorporating humanized immune systems as well as humanized livers with chronic liver injury are reliable surrogates of phenotypes as well as treatment responses observed in patients and enable the testing of questions of clinical importance. To test this hypothesis the proposed project will pursue three aims: (1) to validate a rat HCC PDOX model as a reliable surrogate of responses to eLRT observed in patients; (2) to establish a HIS rat HCC PDOX model that recapitulates responses to combination eLRT and systemic therapies observed in patients and (3) to define a HL rat model that reproduces phenotypes of chronic liver injury observed in patients with chronic liver disease. .

NIH Research Projects · FY 2026 · 2026-04

Summary Actin exists in a dynamic equilibrium between monomeric (G-actin) and filamentous (F-actin) states, forming networks with distinct architectures such as filopodia, lamellipodia, focal adhesions, stress fibers, and muscle sarcomeres. The transition between G- and F-actin, along with the assembly, disassembly, and organization of F-actin networks, is regulated by hundreds of cytoskeletal proteins that specialize in various functions, including filament nucleation, elongation, severing, branching, and cross-linking. Despite significant progress, the molecular mechanisms governing the activities of many of these proteins remain poorly understood. This research program aims to address key knowledge gaps in four major areas: (a) Arp2/3 complex—how does each NPF-binding site contribute individually to Arp2/3 activation? Is coronin-7 an Arp2/3 complex inhibitor or a debrancher, and if so, what is the mechanism? How do factors such as nucleotide state, actin isoforms, and regulatory proteins influence branch stability and mechanosensation? (b) Filament dynamics at the barbed and pointed ends—how do CAP and AIP1 cooperate with cofilin to accelerate filament disassembly? What is the mechanism behind CARMIL- mediated barbed end uncapping? (c) Cytoskeletal mechanisms driving mitochondrial dynamics—what are the structural-functional mechanisms underlying MIRO-mediated recruitment of molecular motors and effectors (TRAK, Myo19, CENPF, and Parkin) to mitochondria? How does Myo19 function in this context? (d) Development of photoswitches targeting cytoskeletal components—how can structural biology and biochemistry be used to design next-generation photoswitches targeting actin cytoskeletal components with greater specificity and efficacy? This research builds on recent successes and expertise reflected in published and preparatory work.

NIH Research Projects · FY 2026 · 2026-04

Africa is the site of origin of modern humans, contains the greatest levels of human genomic variation, and is the source of the worldwide range expansion of modern humans in the past 100,000 years. However, a fundamental gap in knowledge exists regarding African genomic and phenotypic variation, resulting in a lag in biomedical research with relevance to populations of all ancestries. We will apply an integrative evolutionary genomics approach incorporating genomic, metabolomic, proteomic, microbiome, epigenomic, and transcriptomic data in combination with detailed phenotypic data to reconstruct population history and better understand how genetic and environmental variation impacts complex anthropometric, cardio-metabolic, and immune related traits. We will determine the effectiveness of polygenic risk score estimates for these traits developed in non-Africans when applied to Africans and vice-verse and we will study the role of gene X environment interactions on traits. We will use functional genomics approaches to identify causal regulatory loci and to study their impact on gene expression in vitro using high-throughput luciferase reporter assays in appropriate cell lines. We will also use Crispr-Cas9 technology to validate and characterize the functional impact of potential casual variants in both human cells and in vivo in model systems. Lastly, we will characterize gut microbiome diversity and examine correlations with diet, genetic and environmental variation. This study will generate a deeper understanding of human genomic variation, population structure, and patterns of linkage disequilibrium that are critical for the successful application and interpretation of genome wide association studies in multi-ancestry populations. Furthermore, this study will have important implications for understanding the genetic basis of intermediate phenotypes such as gene expression, the metabolome, and proteome. In addition, the data collected will be an important resource for the biomedical research community.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY The germinal center (GC) is a specialized microanatomical structure forming in secondary lymphoid organs in response to pathogens and immunogens. T follicular helper (Tfh) cells are a specialized subset of CD4+ T cells providing help to B cells within GCs. Tfh differentiation occurs in a stepwise fashion, first via polarization during initial priming by antigen-presenting cells and then via interactions with cognate B cells. The GC response provides a two-pronged system to generate durable protective immunity, as its main cellular outputs are antigen- specific memory B cells and long-lived plasma cells. While many key regulators of Tfh differentiation have been identified, many aspects of early Tfh differentiation remain to be elucidated. The Notch signaling pathway is highly conserved from mice to humans and has been demonstrated to play a role in effector T cell differentiation. This pathway is comprised of multiple ligand:receptor pairs which are differentially expressed across cell and tissue types. Of note, a subset of lymph node stromal cells termed fibroblastic reticular cells (FRCs) that are lineage traced by Ccl19-cre have been shown to be essential for both Tfh and effector CD8 differentiation. My own preliminary data indicates the same subset of cells provide necessary signals to antigen-specific, differentiating CD4 T cells within the first three days post immunization to drive the Tfh fate. In the absence of early Notch signals, differentiating T cells adopt a TH1-biased effector fate, evidenced by increased expression of the canonical TH1 transcription factor Tbet and increased production of TH1-associated cytokines such as IL-2, interferon gamma and tumor necrosis factor alpha. My preliminary data also suggests that the key Notch receptor, Notch1, and the key ligand, Delta like ligand 4, are upregulated 24 hours post immunization. Through a uLIPSTIC-based approach where cells in direct contact are irreversibly labeled, I have demonstrated that antigen-specific CD4 T cells interact with Ccl19-cre-expressing FRCs at the same 24 hour timepoint. However, little is known about the exact mechanisms behind receptor upregulation and the direct transcriptional targets following receptor:ligand interactions. Thus, I hypothesize that FRC niches control the early stages of Tfh differentiation and subsequent magnitude of GC responses via spatially regulated access to Dll4 Notch ligands. To explore this hypothesis, I will determine how the upregulation of Notch receptors is regulated post immunization. I will also define how differentiating Tfh cells interact with cellular partners, and how these interactions change in the absence of Notch signaling. Finally, I will determine how the Notch signaling pathway influences the transcription of known Tfh target genes through retroviral transduction and Cleavage Under Targets and Release using Nuclease (CUT&RUN) to identify the direct transcriptional targets of the Notch signaling pathway. Altogether, this proposal will identify direct Notch transcriptional targets in mature T cells for the first time and situate these events amongst the steps of Tfh differentiation, further elucidating the early mechanisms behind commitment to the Tfh fate.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY The consequences of maternal immune activation (MIA) are currently being explored and already show that inflammation during gestation can influence offspring behavior and immunity. However, the influence of paternal immune activation (PIA) on offspring is an understudied topic. Limited studies have shown that paternal immune activation, either through pathogen exposure or stimulation of the immune system with synthetic molecules before conception results in altered offspring behavior. Moreover, these events influence the epigenetic information within the sperm. Yet, we lack understanding of how immune stimulation alters the expression of epigenetic molecules within germ cells and if PIA can also shape offspring immune development. With this in mind, I sought to understand how immune stimulation due to viral infection in male parents could influence offspring immunity. First, I evaluated the impact of viral infection (Zika virus) or immune stimulation with a viral mimetic (Poly (I:C)) on the small RNAs, a carrier of epigenetic information, within sperm. I determined that immune stimulation, with or without viral replication resulted in an altered sperm small RNA profile. I have explored the impact of these modifications have on offspring at two developmental stages: during embryonic development and in juvenile aged offspring. Using sperm from Poly (I:C) treated males to fertilize naïve eggs, I found that gene expression in morula stage embryos was altered, indicating the sperm small RNA profile established by PIA influences early embryonic development. Moreover, when juvenile offspring sired by Poly (I:C) treated males were infected with influenza, I found these offspring had a higher survival rate and fewer signs of infection. Importantly, this is the first evidence that PIA may confer resistance to viral infection to offspring. Taken together, my central hypothesis is that proinflammatory cytokines induced during PIA lead to changes in the sperm small RNA profile which program early embryonic gene expression and confer lasting viral resistance to offspring through altered immune function. For my first aim, I will evaluate if this resistance to infection lasts into adult hood and what differences in offspring immunobiology allow for this resistance. For my second aim, I will determine if paternal immune activation modifies the sperm small RNA profile though cytokine signaling and if these cytokines induced changes are responsible for the offspring phenotypes I have observed. Completion of this proposal will provide new understanding into how paternal immune activation can impact offspring immunity. This study will provide key insights to developmental immunobiology and directly challenge our current interpretation of the evolutionary arms race between host and pathogen.

NIH Research Projects · FY 2026 · 2026-04

The right dorsolateral prefrontal cortex (dlPFC) is increasingly being targeted with transcranial magnetic stimulation (TMS) to reduce anxiety expression in anxiety disorders, depression, and posttraumatic stress disorder (PTSD). There seems to be clear mechanistic evidence that right dlPFC downregulation of amygdala activity should reduce fear and anxiety. Despite this mechanistic evidence, the primary approaches to treat anxiety with neuromodulation involve right dlPFC inhibition. Accordingly, there is a critical need to understand the mechanisms of action underlying neuromodulatory right dlPFC TMS protocols, yet there is not a standardized protocol to yield such evidence. Concurrent TMS/fMRI offers a unique translational perspective for understanding psychopathology. By experimentally stimulating a region of the brain and then directly measuring the activity evoked by this stimulation, it is possible to causally determine the downstream targets of this region, facilitating the development of novel TMS treatments for disorders like PTSD and anxiety. The objective of the current project is to develop a protocol using interleaved TMS/fMRI that can assess the effect of neuromodulatory (potentially therapeutic) TMS protocols on neural and behavioral measures related to anxiety expression. As a proof of concept, we will determine the effect of continuous theta burst stimulation (cTBS) to the right dlPFC on TMS-evoked fMRI responses in anxious subjects. Our central hypothesis is that cTBS of the right dlPFC will drive down activity throughout its downstream targets, resulting in reduced anxiety and greater TMS-evoked deactivations in these downstream circuits. Accordingly, our approach will be to measure anxious arousal and TMS-evoked BOLD responses before and immediately after 1800 pulses of cTBS, or sham stimulation in 140 high anxious individuals using a within-subjects crossover design. Our primary outcome will be TMS-evoked BOLD responses in a network of downstream targets involved in emotion expression (i.e. amygdala, BNST, sgACC). Aim 1 will be to examine the effects of right dlPFC cTBS vs. sham on anxious arousal. Aim 2 will be to examine the effects of right dlPFC cTBS vs. sham on TMS-evoked BOLD responses. Our exploratory aim will be to determine the links between anxiety phenotype, anxious arousal, and TMS-evoked BOLD responses. Our study team features Dr. Desmond Oathes, who is a pioneer in the field of TMS/fMRI, Dr. Lily Brown, who is the head of the Center for the Treatment and Study of Anxiety, and is led by Dr. Nicholas Balderston, who is (to our knowledge) the only researcher who has successfully combined threat of shock with interleaved TMS/fMRI. This study is innovative because it is the first to combine these technologies to study the effect of neuromodulatory TMS on threat-related TMS-evoked BOLD responses. This project is significant because it will provide future researchers with a systematic approach for evaluating the effectiveness of neuromodulatory TMS protocols on several neural and behavioral indices of anxiety expression. It will also yield direct evidence that cTBS can modulate brain activity associated with anxiety.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY For the past decade, my independent laboratory has pioneered the use of gene-editing tools for therapeutic This work has culminated in clinical trials of PCSK9 and ANGPTL3 base editing, with PCSK9 representing the first base-editing therapeutic administered to patients anywhere in the world; initial results from this clinical trial demonstrated durable reductions in blood low-density lipoprotein cholesterol (LDL-C) levels in patients with familial hypercholesterolemia and atherosclerotic cardiovascular disease (ASCVD). Building on this initial success, going forward, I will focus on three exemplary translational challenges in the cardiovascular field: (1) the use of liver-centered, tunable, multiplex editing to safely prevent ASCVD, the leading cause of death worldwide; (2) the use of therapeutic editing to definitively treat inherited connective tissue disorders, such as pseudoxanthoma elasticum (PXE) and Marfan syndrome; and (3) the use of heart-directed therapeutic editing to treat congenital heart disease and inherited cardiomyopathies, empowered by our development of a non-viral approach to deliver editing tools to the myocardium early in life. applications.

NIH Research Projects · FY 2026 · 2026-03

Secure storage of firearms is a critical strategy to prevent suicide, unintentional injury, intimate partner homicide, and gun theft. Forty percent of American households own at least one firearm, and the majority store at least one firearm unlocked. Health systems can promote secure storage through counseling and education, and efforts are most successful when they include distribution of a no-cost secure locking device. Most secure storage programs distribute cable locks, which are inexpensive and convenient for distribution. However, the most common reason for firearm ownership in the U.S. is protection from other people, and firearm owners who value protection also prioritize speed and ease of access to their firearm during a potential emergency. Firearm owners with these priorities are less likely to store their firearms securely, and when offered a choice, prefer to use a lock box over a cable lock. To date, no randomized trials have tested the comparative effectiveness of distributing cable locks vs. providing the firearm owner’s preferred device. Furthermore, little research exists on the effectiveness of secure storage promotion among the range firearm owners, which is especially important as firearm ownership has risen among many demographic groups. This proposal aims to address these gaps in the literature through a hybrid type 1 effectiveness-implementation trial with these specific aims: 1) Compare the effectiveness of distributing cable lock(s) (usual practice) vs. a choice of a lock box and/or cable locks (choice of preferred devices) on participants’ self-reported firearm storage practices; (2) Compare program uptake and storage outcomes across participant demographic, neighborhood socioeconomic, and behavioral and firearm ownership characteristics; and 3) Measure feasibility, acceptability, and appropriateness and identify barriers and facilitators to implementing and scaling the interventions in the study arm among community health sites participating in the trial. The findings will provide insights into factors associated with successful program engagement and secure storage practices and will guide the design and tailoring of future interventions to optimize effectiveness and improve health for all. This study will provide health system and community health stakeholders and policy makers crucial evidence to inform the adoption of secure storage promotion strategies in a range of contexts with high potential for reducing firearm injury morbidity and mortality.

NIH Research Projects · FY 2026 · 2026-03

Abstract This proposal will define a previously unrecognized mitochondrial surveillance mechanism that is essential for the survival of hematopoietic cells under mitochondrial stress. We propose to target this pathway to treat myelodysplastic syndrome (MDS). MDS is a clonal hematopoietic disorder that impairs blood cell production and confers a high risk of progression to acute myeloid leukemia (AML). MDS is commonly caused by somatic missense mutations in splicing factors including SRSF2 and SF3B1. We show that pathogenic mutations in SRSF2 disrupt mitochondrial function, making these cells dependent on a high level of mitochondrial turnover through an organelle specific autophagy pathway termed mitophagy. Inhibiting mitophagy is therefore lethal to SRSF2 mutant cells. Our data show that mitochondrial dysfunction increases expression of the mitophagy activator PINK1 through a posttranscriptional mechanism mediated by alternative splicing. Regulated PINK1 splicing thus represents a new mechanism for sensing mitochondrial stress. We also find that glycogen synthase kinase 3 (GSK-3) is required for PINK1 splicing. GSK-3 inhibitors block PINK1 splicing, impair mitophagy, and selectively kill SRSF2 mutant cells. These findings suggest a therapeutic approach to treat MDS driven by splicing factor mutations. Other perturbations that impair mitochondrial function, including the BCL2 inhibitor venetoclax, also increase PINK1 mRNA stability through GSK-3- dependent alternative splicing. These findings are consistent with recent work showing that increased mitophagy confers resistance to venetoclax. Thus, we find that inhibiting PINK1 splicing with GSK-3 inhibitors impairs mitophagy and increases sensitivity to venetoclax. We propose that GSK-3 inhibitors may be clinically useful in overcoming venetoclax resistance, a common problem in the treatment of patients with hematologic malignancies. Our specific aims are: 1) define how GSK-3 regulates splicing through interaction with spliceosomal components, 2) establish whether GSK-3 inhibition and disrupted PINK1 splicing confer sensitivity to venetoclax in primary patient cells, and 3) test whether clinically well-tolerated mitophagy/autophagy inhibitors are specifically lethal to splicing factor mutant patient cells in vivo.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Effective therapeutics for several fatal neurodegenerative disorders, including frontotemporal dementia (FTD), an Alzheimer's Disease Related Dementia (ADRD) continue to remain elusive. Emerging evidence suggests that TAF15, an important RNA-binding protein (RBP) with a prion-like domain (PrLD), assembles into pathological fibrils in degenerating neurons of ~10% of all FTD cases (i.e., FTD-FET). These findings suggest that aberrant TAF15 phase transitions into pathological fibrils in the neuronal cytoplasm are problematic and difficult to resolve. Agents that prevent and reverse the aberrant phase transitions of TAF15 and restore functional TAF15 to the nucleus in the degenerating neurons of FTD-FET patients are likely to confer therapeutic effects. Indeed, such agents would simultaneously eliminate any toxic gain-of-function of aberrant TAF15 conformers in the cytoplasm, eliminate any prion-like TAF15 conformers that may spread pathology between neurons, and mitigate any toxic loss-of-function caused by depletion of TAF15 from the nucleus. However, TAF15 has been largely overlooked as a therapeutic target. Previously, we have established that short, specific RNAs (~25-34 nucleotides [nts]) provide a novel mechanism to antagonize neurotoxic phase transitions of two related RBPs with PrLDs that are also connected to neurodegenerative disease: TDP-43 and FUS. These short RNAs can engage TDP-43 or FUS, prevent aberrant TDP-43 or FUS phase separation, reverse the formation of existing TDP-43 or FUS aggregates, restore nuclear localization of TDP-43 or FUS, and protect human neurons against TDP-43 or FUS toxicity. Importantly, one short RNA penetrates into neurons, reverses TDP-43 proteinopathy, and mitigates neurodegeneration in mice. These short RNAs are similar in size to FDA-approved antisense oligonucleotides that can be delivered successfully to the CNS of patients to treat neurodegenerative disorders. Here, we propose to extend this approach to TAF15, which has emerged as a more important contributor to FTD-FET than previously appreciated. We hypothesize that short, specific, drug-like RNA oligonucleotides (25nts) can antagonize aberrant TAF15 fibrillization in a neuroprotective manner. Thus, we will pursue two aims: (1) Define RNA oligonucleotides that prevent and reverse aberrant TAF15 phase separation at the pure protein level; (2) Define RNA oligonucleotides that mitigate TAF15 toxicity in neuronal models of FTD-FET. Our studies hold the potential to yield the first therapeutic oligonucleotides that reverse TAF15 aggregation and mitigate toxicity in human neurons in culture. We envision a therapeutic strategy whereby specific short RNA oligonucleotides reverse TAF15 aggregation in FTD-FET and restore functional TAF15 to the nucleus.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Circadian rhythms—daily cycles in physiology and behavior—were long thought to rely exclusively on genetic feedback loops. However, our laboratory has uncovered surprising evidence that these biological rhythms persist in contexts previously considered impossible, including red blood cells that lack nuclei and mice missing essential clock genes. These findings challenge conventional understanding of biological timekeeping and suggest the existence of fundamental timing mechanisms beyond traditional genetic control. Over the past five years, our work has established that metabolic and redox processes can sustain circadian rhythms independently of gene expression, developed novel tools to track these rhythms in real-time, and identified new regulatory factors that maintain rhythmicity even when core clock genes are absent. Building on these discoveries, our research program explores how cells and organisms maintain temporal organization through the integration of genetic and non-genetic mechanisms. We have engineered unique mouse models expressing fluorescent sensors that allow unprecedented visualization of cellular redox states alongside traditional clock gene activity. Using these tools, we investigate how metabolic cycles sustain timekeeping in cells lacking genetic rhythms, how newly discovered regulators coordinate different types of cellular rhythms, and how organisms maintain robust daily timing through redundant mechanisms. This work employs cutting-edge approaches including real-time imaging of single cells, genetic manipulation of model systems, and comprehensive molecular profiling. Our findings are reshaping understanding of biological timekeeping and have direct implications for human health. Disrupted circadian rhythms—whether from shift work, jet lag, or genetic variants—contribute to numerous diseases including metabolic disorders, cardiovascular disease, and cancer. By uncovering new mechanisms that cells use to maintain temporal organization, this research program aims to identify novel therapeutic strategies for treating circadian-related disorders. Our work thus addresses fundamental questions in biology while advancing the NIH's mission to reduce illness and improve human health.

NIH Research Projects · FY 2026 · 2026-03

Project Summary Voltage-gated ion channels are expressed in multiple tissues and are among the most important drug targets for treatment of illnesses including chronic pain, muscular, neurological and cardiovascular disorders. Proper transport and organization of these channels at the plasma membrane is essential for their function. Despite decades of research, there still are fundamental gaps in our understanding of the mechanisms that transport and stabilize these channels at the cell surface. We recently discovered a new candidate protein that may coordinate the transport, stability and activity of voltage-gated sodium (Nav) and potassium (Kv) channels at the plasma membrane – the Golgi-associated phosphoprotein 3 (GOLPH3). The research programs delineated here aim to mechanistically characterize the downstream pathways and effectors that mediate GOLPH3's modulation of Nav and Kv channels, including the recruitment of the scaffold protein Ankyrin-G (AnkG) and the synthesis of glycolipids. We will use a multiscale approach, combining pharmacology, molecular biology, super-resolution microscopy, live fluorescence imaging and electrophysiology, to causally link the subcellular organization and composition of the cell's organelles to ion channel function and cell physiology. We will also use different cellular models, including immortalized cell lines and primary hippocampal neurons, which will allow us to uncover fundamental, conserved mechanisms. We plan to: 1. Define the steps in AnkG, Nav and Kv channel trafficking that are modulated by GOLPH3 and identify the GOLPH3/AnkG interactome, dissecting Golgi dependent and independent mechanisms; 2. Elucidate how glycolipid synthesis influences the function of Nav and Kv channels, dissecting transport mechanisms from modulation of channel conduction. Successful completion of this work will expand our current understanding of fundamental principles that govern ion channel localization and activity across cells. This knowledge may be applied in the future to the development of new strategies to improve ion channel function in multiple diseases, including neurodegeneration and cancer.

NIH Research Projects · FY 2026 · 2026-03

Despite decades of effort, the clinical care of older adults continues to be characterized by poor quality and adverse outcomes. My work to date has focused on identifying goals of care for older adults (what matters), particularly at high-risk and high-cost times in their care trajectory, then trying to align care delivery and payment with those goals. My overall goal for this K24 award is to expand my ability to provide high-quality mentorship to help train the next generation of leaders in research to improve the care of older adults. I plan to accomplish this goal through two primary Aims. First, I will build my capacity to support an effective mentorship program that will support and expand mentees conducting patient-oriented research (POR) to improve care delivery for older adults. This K24 will provide the protected time and infrastructure to allow me to accomplish this Aim through 5 activities: 1) recruit mentees who demonstrate a shared commitment to POR to improve care delivery for older adults; 2) provide research support and mentorship to individual mentees; 3) build my knowledge of geriatrics principles and provide opportunities for mentees, through strong local collaborations, an advisory board of gerontologists and geriatricians, and national training opportunities; 4) develop my skills as a mentor through evidence-based training and structured feedback from both my mentors and mentees; and 5) leverage additional research skills gained through the K24 to grow my research program as a platform to support and expand mentees’ research in POR to improve care delivery for older adults. Second, I will conduct high-impact POR examining optimal ways to implement improved care delivery and payment models that incentivize care around what matters to older adults. I will accomplish this Aim by continuing my current research activities and developing new skills that will enable me to expand my research activities. This K24 will enable me to develop research skills in: 1) using electronic health record data to spur improvements in care delivery; and 2) survey methods, including design, development, sampling, and interpretation of results. I will use these skills to expand my current research seeking to improve the care of older adults in skilled nursing facilities, and propose novel areas of research evaluating the impact of new benefits provided by Medicare Advantage plans on the ability of older adults to “age in place.” These new projects – in addition to data already created as part of funded research– will provide novel datasets, partnerships, and analytic techniques mentees can use to support their own research. My ongoing and proposed research, coupled with my mentorship program to train outstanding investigators in the field, will help address the pressing need to improve care for older adults in health systems in the US. These POR projects will help to align care delivery and payment models with the goals of older adults at high-risk times in their care trajectory, and this approach holds promise for addressing a wide range of care delivery settings and payment models.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY The objective of my research program over the next five years is to advance nucleic acid chemistry and harness in vitro selection (SELEX) techniques to expand the genetic toolkit for RNA silencing and editing, laying a foundation for next-generation RNA therapeutics. RNA silencing and editing hold transformative potential for treating genetic disorders caused by single-point mutations without altering the genetic code. However, current RNA silencers lack sufficient allele specificity, and site-directed RNA adenosine-to-inosine (A-to-I) editing remains in its early stage. To address these challenges, my program focuses on the chemistry, structure, and function of de novo XNAs (xeno nucleic acids)—synthetic nucleic acid analogs with modified backbones that enhance nuclease resistance, extend half-life, and confer unique thermodynamic properties. While chemical backbone modifications have revolutionized RNA therapeutics, they often compromise the natural functionality of catalytic RNAs or aptamers, when incorporated after the evolution process. To overcome these limitations, we are developing an innovative XNA-SELEX platform to generate functional XNA molecules. Over the past five years, I have extensively investigated the effects of chemical modifications on nucleobases and sugar backbones, analyzing their impact on RNA base pairing, self-assembly, and structure. Alongside, I have developed enzymatic and non-enzymatic tools for RNA/XNA manipulation. These efforts form a strong groundwork for creating functional XNAs to address biomedical challenges. Building on this work, we aim to design novel XNAzymes and XNA aptamers based on 3′-NP-DNA (N3′-P5′ linked phosphoramidate DNA) and 2′-F-RNA (2′-fluoro-RNA). These XNAs exhibit enhanced thermal stability, rigid secondary structures, enzymatic resistance, and biocompatibility, making them ideal for allele-specific silencing and precise recruitment of protein enzymes for RNA editing. Their performance will be optimized in cellular models to achieve efficient silencing and editing of disease-associated alleles. In parallel, we will investigate the tertiary structures and folding properties of 3′-NP-DNA and 2′-F-RNA to uncover novel structural motifs and elucidate their functional roles. These findings will guide the design of next-generation XNAzymes and aptamers, expanding their therapeutic potential for RNA targeting and editing. By integrating chemical biology, structural analysis, and functional validation, this program aims to establish a robust platform for XNA-based technologies. The compact size and enhanced stability of XNAzymes and aptamers provide significant advantages for in vivo delivery, addressing key barriers in therapeutic RNA silencing and editing. This work will advance both fundamental insights and translational applications, paving the way for innovative XNA technologies in biotechnology and medicine.