Rutgers Biomedical And Health Sciences

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY Exploring Diverse Mechanisms of Type III CRISPR-Cas signaling Microbes called bacteria and archaea are the most abundant organisms on Earth and play an essential role in our health and well-being. Like us, they use sophisticated mechanisms to defend themselves from viral infection. Our proposed research focuses on molecular mechanisms of adaptive immunity in prokaryotes, which is mediated by CRISPR-Cas systems. These pathways use RNA-guided interference complexes to target complementary sequences in foreign DNA or RNA for degradation, leading to immunity against phages and other mobile genetic elements. Recent studies on widespread Type III CRISPR-Cas systems show that their RNA-guided interference complexes not only degrade nucleic acids, but also produce cyclic oligoadenylates that act as second messenger molecules to activate a network of signaling effectors, including nucleases, proteases, and membrane proteins. While a diverse array of Type III CRISPR signaling effectors have been identified bioinformatically, our understanding of their function and mechanism remains limited. Our lab aims to understand the mechanisms underlying the function and regulation of these signaling effectors, focusing on two major groups: 1) nucleases, which are the largest group of signaling effectors associated with Type III CRISPR systems, and 2) membrane proteins, since they represent a fascinating new frontier of CRISPR-Cas tools and microbial defense biology. We plan to use biochemistry and structural biology to investigate how signaling effector nucleases are regulated by cyclic nucleotide second messenger molecules. Membrane proteins that are associated with Type III CRISPR-Cas systems also suggest intriguing new connections between RNA-guided antiviral immunity and cellular membrane processes in microbes. We hypothesize that CRISPR-associated membrane proteins perturb membrane integrity to cause cell death, and aim to use a combination of biochemistry, cell biology, and structural biology tools to define the function, mechanism, and regulation of these proteins. Taken together, this has the potential to reveal insights that could redefine paradigms for antiviral defense, as well as spur the development of novel point-of-care diagnostics, RNA sensors, and tools for controlling cell behavior.

NIH Research Projects · FY 2026 · 2025-04

Project Summary/Abstract The human brain is remarkably unique in its high capacity to learn and adapt to new environments, which has been attributed to the plasticity of synaptic connections. One form of synaptic plasticity, long-term potentiation (LTP), is associated with AMPA receptor trafficking to the surface of dynamic postsynaptic protrusions called dendritic spines. GluA2-deficient mice show enhanced LTP, supporting that regulation of synaptic surface GluA2 levels is important for LTP expression. However, the mechanism underlying GluA2 trafficking and how this translates to changes in synaptic plasticity is unclear. We have unexpectedly identified a significant increase in synaptic GluA2 in the hippocampi of forebrain-specific conditional knockout (cKO) of partitioning defective 1c (Par1c), also known as microtubule affinity-regulating kinase 1 (MARK1) mice. In addition, these mice exhibit reduced spine formation and impaired spatial learning. This suggests a potential role for Par1c in synaptic plasticity and cognitive functions through regulation of GluA2 trafficking. Importantly, genetic evidence supports that Par1c functions in higher level cognition. Single nucleotide polymorphisms (SNPs) in MARK1 have been associated with autism spectrum disorder (ASD) and bipolar disorder. Furthermore, MARK1 is highly expressed in forebrain pyramidal neurons and exhibits human-specific accelerated evolution, suggesting its importance in the development of cognition. However, the role of Par1c in AMPA receptor trafficking and synaptic plasticity remains unknown. Considering Par1c cKO mice show a significant increase in synaptic GluA2, we hypothesize that Par1c promotes synaptic plasticity by limiting GluA2 trafficking to the spine surface. When Par1c is knocked out, there will be increased synaptic incorporation of GluA2-containing AMPA receptors, leading to reduced spine density and impaired learning. Interestingly, unbiased phosphoproteomic analysis of Par1c cKO hippocampi revealed 7 of 17 significantly dysregulated proteins are associated with endocytic trafficking. Thus, Aim 1 will test the hypothesis that Par1c regulates GluA2 trafficking through phosphorylation of a potential novel target of Par1c identified through phosphoproteomic screen. Aim 2 will determine if synaptic plasticity induction requires Par1c activation using a novel, synaptic-targeted photoactivatable Par1c. The proposed work will elucidate the role of Par1c in regulating AMPA receptor trafficking and synaptic plasticity. Importantly, this project will train the applicant in multidisciplinary techniques including molecular biology, biochemical assays, FRET and FRAP imaging, primary neuronal cultures, and electrophysiology. It will also provide opportunities for the development of critical thinking, written and oral communication skills, and the execution of rigorous and reproducible science. The thorough mentorship and resources available to the applicant combined with her extensive and interdisciplinary neuroscience background will ensure her development into a successful, independent scientific professional.

NIH Research Projects · FY 2026 · 2025-04

ABSTRACT New therapies are needed for dementia and loss of ambulation that are impaired by Alzheimer's Disease and Related Dementia (AD/ADRD) pathologies. Mechanisms underlying pathologies are unclear and pathologies alone do not fully explain cognitive and motor decline. Proteome-wide studies have identified some proteins that contribute to AD/ADRD pathologies and others that more fully account for clinical decline. Yet, the specific CNS functions of many brain proteins requires posttranslational modifications (PTM), the most common being the addition of sugars (glycans). Identifying novel glycopeptiforms underlying AD/ADRD traits to catalyze mechanistic and drug discovery studies are scarce due to difficulties conducting glycoproteome-wide studies. Using our new method, this study will elucidate the role of the glycoproteome in AD/ADRD. It will identify glycopeptiforms related to AD/ADRD pathologies and clinical traits, test if glycopeptiforms link an active lifestyle with brain health and characterize the genetic architecture of the brain glycoproteome and AD. Compelling data support this study. 1) We identified >11,000 unique glycopeptiforms in a glycoproteome-wide study of dorsal lateral prefrontal cortex (DLPFC; N=366). 2) Six glycopeptiforms were related to AD/ADRD pathologies; 3) Eleven glycopeptiforms were related to cognitive decline; 3 were linked with cognitive decline via AD/ADRD pathologies and 8 were associated with cognitive decline but unrelated to AD/ADRD pathologies and may provide resilience. 4) Glycopeptiforms remained related to cognitive decline when controlling for protein abundance in the same model, suggesting a separate effect for the glycopeptiform. 5) GO analyses indicated that glycopeptiforms related to cognitive decline involve metabolic pathways. 6) Applying our bioinformatic analysis identified additional glycopeptiforms related to cognitive decline. 7) The resilience glycopeptiform (pentraxin-2) linked frequent social activities with slower cognitive decline. 8) Numerous common variants impact protein glycosylation; some glycoQTLs are recognized as AD risk variants. This postmortem study will use novel resources already collected from 800 decedents including annual clinical measures, indices of 10 AD/ADRD pathologies, proteome, glycoproteome and Whole Genome Sequencing data. Aims 1-2 will use novel integrative analyses to increase the yield of glycopeptiforms that are related to AD/ADRD pathologies and clinical traits identified in our discovery cohort (n=366). Aim 3a will replicate our findings in a 2nd test cohort (n=434). Aim 3b will increase our power by combining data from our discovery and test cohort. To move beyond simple correlations, Aim 4 will test if the benefits of an active lifestyle are mediated via resilience glycopeptiforms identified in Aim 3b. Aim 5 will examine the genetic architecture of the brain glycoproteome. This study will provide novel high-value targets that may be druggable or underlie resilience behaviors, inform on mechanisms underlying AD/ADRD pathologies and clinical traits and characterize the genetic architecture of brain glycoproteome and AD risk. This study can advance AD/ADRD research and its clinical care.

NIH Research Projects · FY 2026 · 2025-03

ASD is a considered to be the result of complex interactions among genetic and environmental factors, suggesting that the rising incidence of ASD in the past decades can be largely attributed to environmental insults such as maternal infections. However, research using animal models for autism have individually focused on either genetic mutations, pharmacological disruptors or immune activation. The goal of this application is to develop a novel dual-hit mouse model to study gene x environment interactions. Our studies will test the hypothesis that a short increase in the hub cytokine IL-6 during a critical period of neural development will exacerbate the behavioral and synaptic phenotypes in a genetic model of ASD. For these studies we will inject IL-6 into neonatal heterozygous Shank3Δ4-22 mice. While the Shank3Δ4-22 homozygous mice have a penetrant phenotype, the heterozygous mice have only a mild sociability phenotype. Our experiments will test the hypothesis that modestly elevating IL-6 will exacerbate the behavioral and synaptic phenotypes of this genetic model of ASD. Shank3Δ4-22 mice will be administered either PBS or 40 ng rmIL-6 twice daily from P3-P7. We will evaluate male mice as juveniles and as young adults for those core behaviors relevant to ASD (sociability, repetitive behavior, and communication). To assess more complex behaviors the mice will be evaluated using the paired associates learning (PAL) task to evaluate spatial memory, attention and response control, the Barnes Maze, the passive avoidance test to measure avoidance memory and the elevated plus maze to assess anxiety. In Aim 2 we will evaluate the levels of astrocyte-produced proteins that are known to regulate synaptogenesis at P21 and levels of glutamate receptors and glutamate handling proteins. Additional work will evaluate dendritic complexity, spine numbers, spine types and perineuronal nets in the dorsal hippocampus and prefrontal cortex. We anticipate that upon completing these studies, that we will have established a novel dual-hit model for ASD allowing us to gain new insights into gene x environment interactions that are remarkably understudied in the context of autism. This new model will provide conceptual advancements for how gene mutations important for ASD and inflammatory cytokines intersect to affect neuronal maturation and synaptogenesis. The etiology of high functioning ASD, which affects over 40% of people with ASD, remains enigmatic and lacks a relevant animal model. Therefore, we predict that this new dual hit model will be widely adopted by ASD researchers to enable them to identify and test therapeutics for their ability to decrease the penetrance of the negative aspects of ASD while preserving cognitive function.

NIH Research Projects · FY 2026 · 2025-02

Abstract Patients with KRAS-mutated lung cancer have the poorest prognosis and poor response rates to standard cancer treatments. Concurrent LKB1 or TP53 mutations in KRAS-mutated non-small cell lung cancer (NSCLC) define different subgroups of KRAS-mutant NSCLC. There is an urgent need to identify key therapeutical targets in NSCLC. Type I interferons (IFNs), of which the most well-studied are IFNα/β, are known for their anti-viral activities but also play an important role in cancer. IFNε, a unique type I IFN, shares only 30% amino acid homology with IFNα/β and is constitutively expressed in epithelium of mucosal tissues including lung. We have shown that IFNe exhibits distinct functions from IFNa, modulates production of reactive oxygen species and cytokines/chemokines in primary macrophages, and maintains tissue structure and immune homeostasis in mice. Our recent data show that IFNε, overexpressed in cervical cancer tissues, is required for HeLa cell tumorigenic activities and xenograft tumor growth, indicating a novel role of IFNε in tumorigenesis. Moreover, IFNε expression is detected in normal lung tissues and upregulated in KRAS-driven lung tumors. Higher expression of IFNε is associated with poorer survival in lung cancer patients. Given the importance of conventional type I IFNs (e.g., IFNα/β) in tumorigenesis and anti-cancer treatment, understanding the role of IFNε in lung cancer is crucial for identifying new anti-tumor targets. In this proposal, we will determine intrinsic and systemic functions of IFNε in KRAS-driven lung cancer using well-established genetically engineered mouse models of KRAS-driven NSCLC. Our central hypothesis is that aberrant expression of intracellular and extracellular IFNe contributes to lung tumorigenesis by modulating cellular and immune functions. In Aim 1, we will determine the role of tumor-intrinsic IFNε on KRAS-driven lung tumorigenesis. In Aim 2, we will determine the role of systemic IFNε in KRAS-driven lung tumorigenesis. In Aim 3, we will determine whether systemic IFNε deficiency increases the sensitivity of established KRAS-driven lung tumors to immune check blockades. We expect the results of this study will reveal novel cellular and immunological roles of IFNe in KRAS-mutant NSCLC. Identification of IFNe-mediated cellular and immune targets important for tumorigenesis will offer new avenues for development of therapeutic strategies for lung cancer.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY/ABSTRACT Research on the biological origins of psychopathology has largely focused on isolated levels of analyses and discrete illness categories. Moreover, most in vivo imaging efforts only consider a single point in time— essentially ignoring the temporal variability of behavior. To establish illness etiologies, we must account for diagnostic heterogeneity, longitudinal change, and genetic risks. Emerging evidence from large population- based studies of healthy populations indicates that individual differences in behavior are reflected in variability across the collective set of functional brain connections (functional connectome). These data suggest that the spectra of symptom profiles observed in patient populations may arise through detectable patterns of network function, with the disturbance of individual systems preferentially contributing to domain-specific (e.g., executive, affective, and social), but disorder-general, impairments. Critically, genetic factors influence the functioning of large-scale networks. Spatial patterns of gene transcription can show strong correspondence with network topography, potentially driving comorbidity between symptomatically related disorders. However, while recent work suggests a genetic basis for the macro-scale organization of the cortical sheet, the extent to which local cellular profiles may underpin the functional properties of the brain and contribute to associated symptom profiles remains to be established. To address the disconnect between mechanism and nosology, the NIMH strategic plan calls for a bottom-up reappraisal of psychopathology across multiple levels of analysis; facilitating the study of relationships from genes to neural circuits and networks through behavior, cutting across disorders as traditionally defined. Directly addressing these objectives, the proposed research will link individual variation in functional connectomes with longitudinal changes in symptom profiles across unipolar depression, bipolar disorder, and schizophrenia through the combined application of neuroimaging, behavioral, and genomic methods. Building upon our prior work, we will generate individual-level brain-based predictions of multidimensional symptom profiles, defining clinical subtypes by clustering participants according to distinct patterns of functional connectivity (Aim 1). Second, we will map transdiagnostic functional connectome variability to longitudinal trajectories of clinical presentation, deriving predictive models of temporal changes across symptom profiles (Aim 2). Third, we will investigate the cellular underpinnings of the human cortical connectome across health and disease. In doing so, we will identify the cellular associates of network function, establish their relationship to in vivo connectome functioning, and assess co-heritability with illness risk (Aim 3). Linking functional connectomes to individual differences in symptom expression, longitudinal changes in clinically relevant behaviors, and associated cellular and genetic factors represents a tremendous opportunity for the field. The proposed project will enable future advances in our understanding of pathogenesis of affective and psychotic illnesses.

NIH Research Projects · FY 2026 · 2025-02

Project Summary/Abstract Prostate cancer incidence in the United States has significantly increased over the last two decades. Despite the improvement of screening strategies, it remains challenging to accurately identify men at greatest risk of progression to aggressive disease, early enough in the course of the disease to implement appropriate measures that would improve their survival chances. In that respect, prostate cancer is governed by profound disparities with African American (AA) men amongst the highest-risk population groups. Several studies suggest a multifactorial etiology for such disparities, encompassing an accumulation of genetic aberrations. However, genome-based prostate cancer biomarker discovery efforts have largely focused on the nuclear genome, overlooking the smaller but essential mitochondrial genome (mtDNA). Indeed, alterations in mtDNA-encoded oxidative phosphorylation (OXPHOS) genes have been associated with increased prostate cancer risk, particularly in AA men, but their exact functional impact remains unknown. Therefore, understanding the underlaying mitochondrial determinants of prostate cancer disparities could ultimately lead to better precision interceptions and biomarkers for stratifying patients that will develop aggressive prostate cancer. The overarching goal of this proposal is to understand how mtDNA alterations, present in aggressive prostate cancer contribute to disease outcomes in high-risk groups and how to use this knowledge for more effective precision cancer interceptions. In particular, my preliminary data strongly suggest an important role for mitochondrial dysfunction in driving aggressive prostate cancer. Given that among other carcinogenic alterations, adaptations in mitochondrial metabolism may contribute to prostate cancer formation and progression, this proposal will leverage unique prostate cancer mouse models of mitochondrial dysfunction to address specific mitochondrial vulnerabilities for cancer precision interceptions. I hypothesize that mitochondrial dysfunction acts a critical driver of aggressive prostate cancer, and that it can be exploited for interceptive purposes. Specifically, in Aim 1, I will identify mtDNA alterations in mtDNA GEMMs and assess their clinical relevance for prostate cancer disparities. In Aim 2, I will use metformin interception as a proof-of-concept for establishing precision strategies targeting mitochondrial dysfunction in prostate cancer. In Aim 3, I will exploit mtDNA GEMMs to investigate how OXPHOS vulnerabilities are linked to mitochondrial metabolic rewiring in aggressive prostate cancer and, identify novel mitochondrial-related biomarkers to improve precision prostate cancer interception. The career development plan outlined in this award leverages my training at Columbia University and an exceptional advisory committee into an innovative research strategy to guide my career into precision approaches for the interception of aggressive prostate cancer. This proposal will provide the conceptual groundwork, preliminary data, and experimental tools for a competitive R01 submission, thus launching my independent career.

NIH Research Projects · FY 2026 · 2025-02

Summary/Abstract Kidney transplant (KT) survival faces challenges from increased patient complexity, use of non-standard donors, and longer cold ischemic times. Despite refinement in immunosuppression (IS) management over several decades, nearly all KT patients experience progressive loss of allograft function, leading to eventual graft failure while still risking life-threatening IS-related complications. Development of evidence-based IS management practice to optimize long-term KT function has been limited by the need for detailed, longitudinal clinical data for large representative populations. Our previous NIDDK-supported R01 grant (Choosing IS regimens in kidney Transplant by Efficacy and Morbidity; CISTEM), leveraged integrated transplant registry, Medicare claims and national pharmacy clearinghouse data to assess the impact of early IS regimen selection on key post-KT events: infections, malignancy, new onset diabetes, as well as traditional metrics (acute rejection rate, allograft survival and patient death). We developed a free web-based interface to assist transplant professionals and patients in shared-decision making about IS choice at the time of KT. However, IS requires lifelong dynamic adjustments. We will enhance our prior work with the following Specific Aims in CISTEM2: 1) Recognizing the lack of longitudinal and granular clinical observations and lab results, we will establish a novel CISTEM2 dataset, integrating: a) national transplant registry data granular clinical data from 12 transplant centers housed in the Greater Plains Collaborative (GPC,) a component of the Patient Centered Clinical Research Network (PCORnet); b) administrative claims; and c) social determinants of health (SDOH) indicators for KT recipients. GPC utilizes the PCORnet common data model (CMD) for all clinical data, which can be securely linked to national transplant registry, administrative claims and SDOH indicators. We will expand from the multivariable propensity and Cox proportional hazard models with time-varying covariates used in CISTEM, to more responsive and clinical meaningful endpoints such as percentage drop in KT function (via estimated glomerular filtration rate; eGFR) and the validation of computed phenotypes for key clinical events. 2) We will extend CISTEM by developing longitudinal machine learning (ML) algorithms to dynamically identify IS strategies that optimize longer-term KT eGFR, reduce cost, and limit those IS comorbidities that post-transplant patient focus groups identify as contributors to diminished quality of life. 3) We will validate the predictive models refined in Aim 1 and the ML models developed in Aim 2, using two additional PCORnet sites (12 more KT centers; Total N: 40,535 KTs). We will analyze PCORnet CDM from all centers using distributed learning models to refine the first dynamic, evidence based clinical decision tool for longitudinal IS management after KT. Balancing the risk of acute rejection, patient and graft survival, and risk of IS-related complications after KT, based on highly granular, multicenter, longitudinal clinical data from real-world patient experience, will allow patients and physicians to dynamically optimize IS in a more personalized, patient focused, and cost-effective manner.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY/ABSTRACT This K01 proposal integrates research and training to address gaps in our understanding of the associations between substance use disorders (SUDs) and other forms of psychopathology. Extant research has consistently demonstrated that SUDs share phenotypic and etiologic variance with other forms of psychopathology, such as externalizing and internalizing. Despite this, most research into the classification and etiology of SUDs treats them as isolated from each other and other forms of psychopathology. A clearer understanding of the ways in which SUDs covary, both phenotypically and genetically, is essential to increase specificity of SUD phenotypes, which can be used as targets in future research, and which can improve classification and treatment in clinical settings. The overall goal of this award is to facilitate Dr. Poore’s development as an independent scientist working at the intersection of psychiatric nosology, statistical genetics, and translational science to uniquely equip her to address these research questions. The proposed training integrates Dr. Poore’s background in clinical psychology and classification of psychopathology with training in substance use, advanced statistical genetics methods, and translational research skills. The following training objectives will be completed during the award period to accomplish these goals: 1) training in the interface between SUDs and internalizing psychopathology; 2) training in biological annotation of genetic variants and multi-ancestry statistical genetic methods; 3) integrating basic and clinical research; and 4) gaining professional competencies essential for independence.The research aims proposed in this K01 use multiple analytic approaches to understand the relationships between substance use disorders and other forms of psychopathology and the extent to which better classification can improve prediction of treatment response in a treatment seeking population. These analyses will rely on several sources of data, including large, deeply phenotyped samples that include broad measures of psychopathology and relevant outcomes, previously published genome-wide association studies of psychiatric disorders, and data collected from individuals seeking treatment at the Rutgers University Behavioral Health Center to accomplish the following aims: 1) Use advanced quantitative methods to model the phenotypic overlap between SUDs and other forms of psychopathology; 2) Identify and characterize genetic variants that influence SUDs and other forms of psychopathology; 3) Quantify the clinical utility of phenotypic and genetic psychopathology clusters.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY Cigars carry many of the same health risks as cigarettes yet have historically been subject to fewer regulations. For instance, while cigarettes must be sold in packs of at least 20 and are only available in one characterizing flavor (i.e., menthol), the cigar market is much more diverse, with cigar products available in a variety of flavors, packaging sizes, and styles. Not coincidentally, there have been increases in cigar sales over the past decade, while cigarette sales continue to decline. Cigar pack size is a modifiable factor that may facilitate addiction and influence patterns of cigar use. Existing research suggests that small cigar pack sizes are inexpensive, appeal to vulnerable, price-sensitive populations, and may facilitate experimentation, while larger pack sizes may increase consumption and delay cessation among more established users. However, this body of research is scant and there is a need for more research on the cigar marketplace and the impact of cigar pack size on product appeal, intentions, and use. As such, we propose a series of complementary studies to fill these gaps in the literature. Specifically, this project aims to: 1) characterize changes in cigar pack size over time and assess its impact on sales, consumption, and patterns of use using secondary data sources (i.e., Nielsen and the Population Assessment of Tobacco and Health Study); and 2) examine how pack size, price, and flavor affect product preferences among heterogenous populations via two discrete choice experiments. This research will provide rigorous empirical data to advance the science on the underlying mechanisms of the associations between cigar pack size and use across geographic and sociodemographic groups.

NIH Research Projects · FY 2026 · 2025-02

PROJECT SUMMARY Magnesium (Mg2+) is the fourth-most abundant ion the human body. Participating in over 300 enzymatic pathways, intracellular Mg2+ is crucial for life, affecting fundamental cellular process such as metabolism, DNA replication, mRNA transcription and protein translation. Consequently, the amount of intracellular Mg2+ in cells and in the body are tightly regulated, within narrow sub-millimolar ranges. Alterations in Mg2+ homeostasis are associated with numerous clinical phenotypes, including cardiovascular disease, diabetes mellitus, hypertension as well as neuropsychiatric and neurodevelopmental disorders like anxiety, intellectual disability and developmental delay. Cyclin M2 (CNNM2) is a transmembrane protein that mediates cellular transport of Mg2+. The protein is highly expressed in the kidney and the brain, where it is principally expressed in neurons. Proteomic studies by the Runnels laboratory have demonstrated that CNNM2 is part of protein complex. Human mutations in CNNM2 give rise to a monogenic disease called Hypomagnesemia, Seizures, and Intellectual Disability (HSMR) Syndrome. HSMR patients excrete more Mg2+ from the kidney into the urine, causing Mg2+ deficiency, are also obese and have seizures, motor skills difficulties, intellectual disability and developmental delay. The HSMR symptoms are consistent with intracellular Mg2+ levels being critical for neuronal development and function. The importance of intracellular Mg2+ in neurobiology is supported by a wealth of literature, but surprisingly despite its significance, Mg2+ homeostasis remains poorly understood in neurons. Moreover, CNNM2 neuronal expression and its protein composition remains undefined. We will address this gap in knowledge and hypothesize that i) mouse and human CNNM2 will have a specific neuronal expression and protein composition and ii) CNNM2 mutations will disrupt Mg2+ flux in both mouse and human neurons, and be associated with developmental, synaptic and proteomic changes that are rescued once intracellular Mg2+ levels are restored. To test this hypothesis, in Aim 1 we will determine i) Cnnm2 expression in the developing and adult mouse brain using complementary approaches (IHC, western, GFP transgenic) and ii) the composition of CNNM2 complex in moue and human induced neurons (iNs). In Aim 2, we will rigorously define the function and impact of CNNM2 isogenic KO and HSMR disease-causing mutations on neuronal development and function. Mg2+ levels, neurite and synaptic development, and Ca2+ signaling will be examined in mouse and human iNs. Proteomics will determine expression changes and rescue experiments will uncover which phenotypes are Mg2+ specific. By using both mouse and human stem cell lines, we will be able to determine whether CNNM2 function is conserved across species. Unbiased, high throughput methodologies (robotics, high content CellInsight imaging platform, proteomics) will be utilized to increase productivity, statistical power and rigor. These studies will provide critical understanding of how intracellular neuronal Mg2+ homeostasis is maintained and how its disruption affects neuronal function and development and contributes to CNS disorders, including epilepsy and HSMR.

NIH Research Projects · FY 2026 · 2025-01

Chronic kidney disease (CKD) affects 40% of older adults (≥65 years), and is a significant contributor to morbidity, mortality, and healthcare spending. Although older adults with CKD are more likely to be diagnosed with multiple chronic conditions, take multi-drug regimens, and owing to pharmaco- dynamic and -kinetic modulations, are uniquely susceptible to experiencing drug-related harms, they are routinely excluded from clinical trials. Thus, there is an urgent need to examine the safety and effectiveness of medications in this population. In response to this unmet need, this proposal will study the effects of medications in older CKD adults. We will focus on cardiometabolic drugs as such factors are the most frequent complications of CKD (e.g. cardiovascular diseases [CVD]). Specific medications were selected for study based on the criteria of high and rising prevalence of use, potential for fatal harms, concerns for ineffectiveness, and unmet clinical need. We will primarily use the national Veterans Affairs data, and externally validate findings in a large EHR database. Aim 1 will evaluate the role of renoprotective therapies (e.g. angiotensin converting enzyme inhibitors; ACEi) in sustaining long-term kidney function among patients initiating: ACEi vs other antihypertensives (Aim 1a), and sodium-glucose co-transporter-2 inhibitors vs other glucose-lowering therapies (Aim 1b). Aim 2 will elucidate the benefit-risk profiles of newer CVD medications by comparing the incidence of CVD endpoints and major bleeding in patients initiating: direct acting oral anticoagulants vs warfarin (Aim 2a), and newer antiplatelet drugs (e.g. ticagrelor) vs clopidogrel (Aim 2b). Our central hypotheses are that (a) due to a confluence of factors (e.g. low prevalence of proteinuria), renoprotective medications have limited effectiveness in sustaining kidney function; and (b) kidney disease and older age alter the benefit-risk profiles of medications. The expected impact of this proposal is significant as it will generate the requisite evidence base to support drug prescribing in this critically understudied population, impacting 40% of older adults who have CKD. Given the paucity of data from clinical trials, these findings will serve as the primary source of drug information for patients, caregivers, and clinicians to make informed decisions. We believe that this proposal outlines the most effective, valid, and feasible way to generate clinically relevant evidence pertaining to medication effects in older adults with CKD.

NIH Research Projects · FY 2026 · 2025-01

Project Summary/Abstract Blood pressure is controlled mainly at the arterioles in the microcirculation. The endothelium plays a critical role in controlling function of the vessel by the production of vasodilators as vasoconstrictors agents. In arterioles the main vasodilator agents are nitric oxide (NO) and endothelium-derived hyperpolarization (EDH) by direct activation of Ca2+-activated K+ channels (KCa) of small (SKCa) and intermediate (IKCa) conductance which cause vasodilation in resistance arteries. NO and EDH require endothelium Ca2+ increases. NO modulates endothelial cell function via either guanylyl cyclase 1 (GC1) or protein S- nitrosylation. While much attention has focused on GC1-associated vasodilation, the role of endothelium evoking S- nitrosylated on calcium permeable channels which will be critical to regulate the vasomotor tone is an interestingly mechanism that has not been fully explored yet. TRPV4 has been described as an essential component in the endothelial Ca2+ increases, promoting an influx of Ca2+ from the extracellular space under shear stress or upon endothelium dependent vasodilators. Thus, TRPV4 activation is critical to promote NO and EDH-driven relaxation. However, even after TRPV4 activation by vasodilators or specific TRPV4 agonists, the endothelial Ca2+ influx and EDH-driven relaxation are dramatically diminished by blocking Cx43 hemichannels. This implies that: 1) TRPV4 is necessary but not sufficient for proper endothelial Ca2+ entry, EDH and dilation; 2) TRPV4-stimulated dilation crucially involves endothelial Ca2+ entry via Cx43 hemichannels. In this context, recent results indicate TRPV4-induced Cx43 hemichannels opening in lens epithelium. Our preliminary results in arteriolar endothelial cells (primary culture as intact endothelium) revealed TRPV4-induced endothelial Cx43 hemichannels activity, endothelial Ca2+ influx, and endothelial hyperpolarization by Cx43 hemichannels activation. Connexin hemichannels form two types of channels. Gap junction channels and hemichannels. Connexin proteins in non-junctional plasma membrane allow tightly regulated extracellular Ca2+ influx in astrocytes, muscle cells, microglia, cardiac cells, etc. Endothelial peripheral arterioles cells express connexin (Cx) 37,40 and 43. However according to our previous data and preliminary results using primary culture endothelial cells, isolated mesenteric arteries the S-nitrosylated Cx43 hemichannels is a critical component in the TRPV4/Cx43 hemichannels signaling. The objective of this proposal is to identify the mechanisms through which TRPV4 activates endothelial Cx43 hemichannels which will be a critical step to trigger Ca2+ increases promoting endothelial hyperpolarization. In addition, we want to test whether i n h y p e r t e n s i o n m o d e l s t h e r e i s a dysregulation of T R P V 4 / Cx43 hemichannels s i g n a l i n g . Besides, we postulate that interaction TRPV4-induced Cx43 hemichannels currents which evoke Ca2+-activated K+ channels (KCa) of small (SKCa) and intermediate (IKCa) conductance promoting endothelial hyperpolarization. Our central hypothesis is that S-nitrosylation of endothelial Cx43 hemichannels by TRPV4 activation is required for the Ca2+ entry, endothelial hyperpolarization and vasodilation upon endothelium-dependent agonist. We will test this hypothesis through two mechanistic Specific Aims (SA): • SA1 Is a TRPV4/Cx43 hemichannel signaling node a key component in arteriolar dilation? • SA2 Do hypertensive mice display a dysfunction in endothelial TRPV4/Cx43 hemichannel activity? These novel studies will yield mechanistic insights into the role of endothelial Cx43 hemichannels. They will also advance knowledge of vascular disease and assist physicians to manage hypertension.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY The 2016 Deeming Rule extended FDA’s regulatory authority to cigars, including cigar labeling and marketing. Cigars pose similar health risks as cigarettes but are far cheaper and disproportionately used by young people and minorities, particularly Black and African Americans. Prior research has shown cigar packaging features such as color and flavor descriptors can influence favorable cigar perceptions and use intentions, but little is known about the effects of “natural” descriptors in cigar marketing, which appear to be growing in use and may mislead consumers into thinking these products pose lower risks. Evidence from cigarette literature has documented misleading effects of “natural” descriptors, leading the FDA in 2015 to order makers of Natural American Spirit cigarettes and other cigarette brands to cease use of the “natural” descriptor in their advertising. While FDA can extend similar restrictions to cigars, cigar-specific data is needed to examine whether similar misleading effects of “natural” descriptors occur in the cigar marketing domain to inform any potential regulatory actions. This project will use complementary methods to extend the evidence base regarding use of “natural” descriptors and imagery to cigar packaging, including its prevalence, growth and impact on young adults’ attention, cigar perceptions (including risk perceptions), appeal, and use intentions. In Aim 1 we will analyze Nielsen cigar sales data and purchased cigar packs over the project period to examine use of various “natural” themed descriptors (both explicit and alternative) and imagery (e.g., tobacco leaves) on cigar packaging over time. Under Aim 2 we will test the effects of “natural” descriptor types and imagery on cigar packaging (as well as interactions with cigar product images) on young adults’ cigar product perceptions and use intentions using an online experiment with young adults (ages 18-34) who currently use cigars and non-users susceptible to cigar use. We will also conduct a second exploratory online experiment examining the interaction between “natural” descriptors/imagery and potential health communication messages on cigar packs (i.e., text and pictorial warning labels, and “natural does not mean safer” disclaimers). We will complement our Aim 2 study results by examining likely real-world attention to “natural” descriptors and imagery through an in-person eye-tracking study with 160 young adults (Aim 3). This study will inform FDA research priorities on Marketing Influences, Communications, and Behavior, and relevant cigar regulatory actions.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY Ribosomes are molecular machines made of protein and RNA that synthesize proteins. The biogenesis of new ribosomes is amongst the most energetically costly processes in the cell, accounting for ~60% of all ATP consumed. Ribosome biogenesis is dysregulated in a series of diseases known as ribosomopathies, and upregulated in proliferative cancers. However, the molecular mechanisms underlying ribosome biogenesis – how ATP-driven mechanoenzymes (force-producing enzymes) sequentially convert ribosomal precursors into mature particles – remain poorly understood. The knowledge gap is especially prominent in human systems, as most studies on ribosome biogenesis to date have focused on yeast model systems using top-down approaches. The overall vision for my research program is to fill this gap in knowledge; to mechanistically characterize the enzymology of human ribosome biogenesis, to reconstitute ribosome biogenesis steps in vitro, and to integrate the knowledge and assays developed to enable new treatments for ribosomopathies and cancer. Over the next five years, we will focus on the subset of mechanoenzymes from the AAA (ATPase associated with diverse cellular activities) superfamily. Building upon our expertise in single-molecule optical tweezers, we will develop assays to determine how these mechanoenzymes use ATP-dependent conformational changes to generate force. Using bottom-up biochemical reconstitution, we will determine how autoinhibited AAA mechanoenzymes become activated by cofactor binding, how AAA activity is targeted at specific pre-ribosomal substrates, and how force-producing conformational changes are coupled to pre-ribosomal maturation. We will furthermore use small molecule inhibitors of these AAA enzymes to stabilize transient conformational states and to identify how the several ATPase active sites present per molecule coordinate their activities. Initial assays will use yeast AAA orthologs, before advancing to the human orthologs to study how AAA cofactors unique to the human system integrate into the overall mechanisms. We will also study how ribosomopathy-associated mutations in human AAA enzymes affect their function. Ultimately, this work will characterize the core enzymology of AAA-driven ribosome biogenesis steps, will build a molecular understanding of associated ribosomopathies, and will pave the way towards developing AAA-targeting anti-cancer therapeutics.

NIH Research Projects · FY 2026 · 2025-01

Project Summary/Abstract The heart has a distinct metabolism that supports the continuous pumping of blood. This includes maintaining the pyruvate-lactate axis. This metabolic axis describes the interrelation between three critical metabolic nodes: central carbon metabolism in the cytoplasm, oxidative phosphorylation in the mitochondria, and lactate abundance in the extracellular milieu. During heart failure, this metabolic axis is imbalanced by increased glycolytic flux coupled to decreased pyruvate oxidation and increased lactate export. In newly published data, I demonstrated that inhibiting lactate export in the heart, was sufficient to rebalance this axis and mitigate cardiac hypertrophy and heart failure in mice. Suggesting that retaining lactate within the heart is beneficial to its health. This is further supported by the fact that healthy hearts are net consumers of lactate. Yet, lactate metabolism remains ill-defined and poorly studied within the heart. This proposal seeks to quantitatively characterize lactate metabolism in the heart and to test the hypothesis that myocardial lactate production and consumption is integral to cardiac health by balancing and maintaining the pyruvate-lactate axis in the heart. In my K99 Aim 1, I will use isotope tracers to quantify lactate production and consumption fluxes in normal cardiomyocytes and hearts. In my K99 Aim 2, I will define the metabolic rewiring of the pyruvate-lactate axis in chronic heart failure patients undergoing left ventricle assist device (LVAD) therapy that have been infused with 13C-glucose and compare failing and recovering human hearts. I will also infuse HF mouse models with 13C-glucose and treat them with the MCT4 inhibitor VB124, to determine if VB124 is a suitable treatment for LVAD HF patients. In my R00 Aim3, I will build a research program centered around comprehensively understanding how lactate metabolism is regulated, and how it impacts hypertrophic cardiomyopathy (HCM). Collectively, these experiments will lay the groundwork for targeting of lactate metabolism as a new therapeutic approach in cardiac hypertrophy and heart failure. Under the guidance of my primary mentor, Co-mentor and my team of collaborators during the K99 period, this proposal will allow me to successfully transition from my current mentored position into an independent research group leader.

NIH Research Projects · FY 2025 · 2025-01

ABSTRACT Aging is a complex biological process that significantly impacts tissue and organ physiology, particularly the vascular system. This decline in vascular function is a major risk factor for various chronic diseases, including cardiovascular diseases, stroke, neurodegenerative disorders, obesity, sarcopenia, osteoarthritis, and cancer. Endothelial cell senescence, characterized by loss of function and increased secretion of harmful factors, contributes to vascular dysfunction. These changes are driven by processes such as inflammation, oxidative stress, and alterations in signaling pathways, leading to molecular changes and the accumulation of senescent endothelial cells. Detecting these changes involves assessing differential expression and localization of extracellular proteins in vascular endothelial cells (VECs), which are crucial in age-related vascular dysfunctions. To enhance our understanding of these molecular mechanisms and age-related pathologies, innovative techniques for imaging molecular and cellular alterations are needed. In vivo phage display has translational potential for identifying aging markers and VEC targeting ligands. Our team has successfully identified peptide ligands for various biological processes, including cancer, obesity, atherosclerosis, trauma, and retinopathy. In this proposal, we aim to isolate and characterize peptide ligands targeting VECs in young versus aged mice in vivo and senescent versus non-senescent murine VECs in vitro. Our preliminary data from aged mice tissues reveal thousands of shared and tissue-specific peptide ligands. Aim 1 involves additional biopanning in young mice for comparison with aged animal peptides. Aim 2 focuses on identifying peptide ligands specific to senescent VEC receptors through further biopanning. Aim 3 aims to validate the specificity of promising peptide ligands in cells and tissues, identifying their receptors and evaluating their expression in aged tissues. Completing these aims will provide an innovative approach to study vascular aging, potentially paving the way for senolytic drug development or targeting strategies for age-related vascular dysfunction-related diseases.

NIH Research Projects · FY 2025 · 2025-01

Synapse loss is an early event in Alzheimer’s disease (AD), which may explain some of the earliest cognitive symptoms seen in these patients. Macroautophagy, herein referred to as autophagy, is a lysosome mediated degradation pathway that plays a specialized role in the synapse and, thus, may be important for learning and memory. Autophagy is also implicated in the pathogenesis of AD. The precise role of autophagy in AD is still unclear, but there is evidence that autophagic processing of synaptic proteins is disrupted in the course of AD. This proposal aims to investigate how AD-associated pathogenesis interferes with synaptic autophagy and if specifically targeting synaptic autophagy can be neuroprotective in an AD mouse model. Aim 1 will utilize primary hippocampal cell cultures derived from the APPNL-F/NL-F mouse model of AD to determine which step in the autophagic processing of synaptic proteins is disrupted by AD-associated pathogenic changes. Aim 2 will evaluate if optimizing synaptic autophagy by over-expressing the proteins Rab26 and/or Bassoon in the mouse brain is protective in APPNL-F/NL-F mice. To pursue these aims, this proposal incorporates biochemical, histochemical, cell biological, genetic, and behavioral approaches in mouse models and primary neuronal cultures. The data collected will provide insight into how AD-associated pathogenic changes contribute to disruption of synaptic autophagy, and if optimizing synaptic autophagy can be protective in AD.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY As the most common birth defect, congenital heart disease (CHD) is a prevalent health concern. Some of the most severe and life-threatening CHD arise in the arterial pole, where a subpopulation of mesodermal progenitors called the second heart field (SHF) contribute to the myocardium of the outflow tract and right ventricle. Children with CHD are prone to debilitating lymphatic conditions including plastic bronchitis, lymphedema, chylothorax, and protein-losing enteropathy. However, insufficient research into the lymphatic system in the context of CHD has been conducted. To determine the basis of lymphatic dysfunction in patients with CHD, I focus on understanding the development of the bilateral bicuspid lymphovenous valves (LVVs), through which interstitial fluid collected by lymphatics drains into the venous circulation. LVVs are necessary gatekeepers at the junction of lymphatic ducts with veins and their absence results in primary lymphedema and blood-filled lymphatics. Our preliminary data suggest that the SHF contributes not only to cardiomyocytes but also to LVVs. I expect this work will establish the SHF as a common precursor of the lymphatic and cardiovascular systems. Through my specific aims, I plan to determine 1) when SHF-derived cells contribute to developing LVVs and if they do so through a venous intermediate and 2) if this contribution is required for proper LVV formation. In my first aim, I will use constitutive and inducible Cre-loxP technology, intersectional fate mapping, and immunofluorescence staining of mouse embryos to genetically trace SHF cell lineage and fate map SHF progenitors. In my second aim, I will utilize conditional knockout mouse models and immunofluorescence staining to determine if SHF progenitors are required for LVV development. I will investigate if defects in the SHF precipitate abnormal LVV development in a mouse model of the human disease 22q11DS, which presents clinically as SHF-related heart defects and can be accompanied by lymphedema. Completion of the studies described in this proposal will provide novel insight into the development of lymphatics, the cellular origin of the LVVs, and lymphatic defects in CHD patients. My findings will lead to improved screening and treatment of potentially life-threatening lymphatic defects in CHD patients. The proposed project will be carried out in a well-equipped laboratory at Rutgers New Jersey Medical School, guided by a sponsor with a strong record of research contributions to vascular development in the context of congenital heart disease. The sponsor has mentored numerous graduate students to success and brings a wealth of experience to the project. The PI will utilize her previous training in developmental biology, supplemented by new skills in lineage tracing and quantitative analysis of three-dimensional confocal datasets. Her training plan outlines achievable objectives in field-specific research training, dissemination of findings, clinical experience, mentoring, and professional development.

NIH Research Projects · FY 2026 · 2024-12

Project Summary Gut microbiome products such as indole and phenol metabolites have major impacts on host physiology. Decreased production of these important metabolites is linked with many diseases, and increasing circulating concentrations of indole or phenol metabolites ameliorates inflammatory bowel disease or obesity in mouse models, respectively. Diet is a promising tool for treating microbiome-related diseases, as dietary modifications can affect both microbial composition and metabolism, but dietary control of indole and phenol production is still underexplored. Here, this work will dissect the effect of dietary components such as protein, fiber, and processing on microbial production of phenol and indole metabolites. The overarching hypothesis driving this work is that diet controls microbial metabolism through altering the balance of dietary or secreted protein available to the microbiome. Aim 1 will investigate the effect of protein digestibility and dietary processing on microbial metabolites. Liquid chromatography-mass spectrometry (LC-MS) will be used to measure circulating and fecal metabolites and 16S rRNA sequencing will be used to measure microbial composition in mice fed differentially processed (e.g. cooking, grinding) diets. Additionally, the contribution of dietary protein fermentation will be directly measured via 13C-labeled protein diets. Aim 2 will examine the effect of dietary fiber and mucin production on microbiome metabolism. Through isotope tracing and techniques developed by the Rabinowitz lab, and we will measure the contribution of microbial fermentation of host-secreted proteins to microbial metabolites. Additionally, dietary fiber can impact both the production of host-derived mucin as well as the abundance of bacteria that can ferment the mucin. In mice fed diets with different types of fiber (e.g. inulin, pectin, cellulose), mucous layer thickness will be measured through histologic staining, microbiome composition will be assessed by 16S rRNA sequencing of fecal samples, and metabolite concentrations in feces and serum will be analyzed via LC-MS. Completion of the work proposed here will provide a critical foundation for the understanding of dietary control on production of indole and phenol metabolites. By unlocking the potential for targeted dietary control of desired metabolites, this work could eventually facilitate dietary formulations to help treat patients suffering from microbiome-related diseases such as inflammatory bowel disease and obesity.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY The per- and polyfluoroalkyl substances (PFAS) are human-made organic compounds that are widely used in consumer and industrial products. The strong C-F bonds of PFAS make them highly resistant to environmental degradation and thus earn PFAS the name “Forever Chemicals. Humans can be exposed to high levels of PFAS through drinking water and foods in areas near the contaminated sites. PFAS are rarely metabolized once absorbed, with half-lives as long as 8-9 years. Epidemiological evidence revealed associations between PFAS and female ovarian disorders, such as premature ovarian failure (POF), irregular menstrual cycles, and infertility, but the underlying mechanisms remain elusive. So far, nearly all studies focused on perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), two long-chain legacy PFAS that have been phased out. The ovarian toxicity (ovotoxicity) of other widely used long-chain PFAS such as perfluorononanoic acid (PFNA) are rarely studied, despite some may have similar or even higher contamination levels. In the real world, humans are exposed to PFAS mixtures, but their ovarian impacts are poorly characterized. Our recently published studies and preliminary data support ovotoxicity of PFAS. (1) A cross-sectional epidemiological analysis of the NHANES dataset revealed positive associations between serum concentrations of long-chain PFAS and long-term amenorrhea in women of reproductive age; (2) In an in vivo mouse exposure model, PFNA accumulated in the ovary to levels observed in women, and PFNA dose-dependently inhibited ovulation; (3) In an in vitro mouse ovarian follicle culture system, PFNA concentration-dependently inhibited follicle maturation and ovulation; and (4) A selective antagonist of peroxisome proliferator-activated receptor gamma (PPARγ) rescued PFNA-blocked ovulation in both in vitro and in vivo models. With these findings, we will test our central hypothesis that: (1) at environmentally high but human-relevant exposure levels, PFNA acts primarily as a PPARγ agonist, as the molecular initiating event (MIE), in follicular granulosa cells to interfere with folliculogenesis, leading to impaired ovarian functions and female reproduction; (2) also via PPARγ-mediated MIEs, PFAS of major public health concern and their mixtures produce similar ovotoxic effects but with different potentials. We will integrate in vivo, in vitro, and in silico models to test our hypotheses in three Specific Aims. In Aim 1, we will use a mouse model of natural ovarian cycles and human-relevant doses and duration of PFNA exposure via drinking water to investigate ovarian disrupting effects of PFNA and female reproductive outcomes. In Aim 2, we will study the mechanistic and causal roles of PPARγ in PFNA-induced ovarian follicle maturation and ovulation defects. In Aim 3, we will use experimental and computational models to determine the ovotoxicity of PFAS singles and mixtures of major health concern. This research is highly innovative and significant given the emerging concern of PFAS on female reproduction. Elucidating the ovotoxicity of PFAS will enable us to speed up the development of prevention, mitigation, and remediation methods to protect female reproductive health and fertility.

NIH Research Projects · FY 2026 · 2024-12

Project Summary Approximately every 40 seconds, an American suffers from acute myocardial infarction (AMI), with over 25% of AMI patients dying within one year of hospitalization. Although several strategies are available to help risk-stratify patients with AMI, the existing clinical risk scores have only modest accuracy. This research aims to fill this gap by providing non-invasive and objective prognostic quantitative imaging markers for personalized risk stratification for AMI patients. Our preliminary clinical data support that cardiac ultrasound radiomics−a mathematical framework that converts standard of care cardiac ultrasound images into minable high-dimensional data−can identify patients at high risk for hospitalization for adverse cardiac events. However, progress in developing these novel markers is limited by a lack of optimization, standardization, and validation−all critical barriers to clinical use. Leveraging the existing imaging and clinical database of patients admitted at several hospitals within our Health System, we have assembled a multidisciplinary team of expert physicians, imagers, and engineers to facilitate the development and validation of the proposed technology. Our central hypothesis is that integrating cardiac ultrasound radiomics, conventional echo, and clinical data using deep learning is incremental to the currently recommended strategies in determining phenotypic presentations and prognosis in AMI. Specifically, we will (1) we will benchmark cardiac ultrasound radiomics-guided deep neural network model to conventional risk assessment (GRACE 2.0 score, EF) in predicting 1-year risk of all-cause mortality as the primary endpoint. We will develop a new Cardiac Ultrasound Radiomics Exploration in AMI (CURE-AMI) probability score that integrates radiomics with laboratory and clinical data to identify a high-risk AMI phenogroup, (2) in a prospective cohort study of patients presenting with non-ST elevation acute coronary syndrome, we will assess if point of care cardiac ultrasound (POCUS) radiomics compared to regional and global left ventricular function assessment improves the identification of high-risk coronary anatomy, including the presence of acute coronary vessel occlusion, and (3) in a prospective cohort study of patients presenting with AMI, we will assess whether a parametric display of ultrasonic radiomics features compared to conventional echo parameters will better estimate infarct size and location using paired blinded CMR assessment. Combined with our rich previous experience in developing machine-learning algorithms, this application is a unique opportunity to utilize radiomics for stratifying one of the most common problems in healthcare. Successful completion of our aims will help risk- stratify AMI patients along the healthcare continuum, from early diagnosis and institution of time-sensitive therapies to personalized care of those who remain at substantial risk for long-term MACE.

NIH Research Projects · FY 2026 · 2024-12

Epithelial ovarian cancer remains the most lethal gynecological malignancy in the United States, where the 5-year overall survival rate for patients with high-grade serous ovarian cancer (HGSOC) remains dismal at 34%. While the infiltration of T cells into ovarian tumor islets is clearly associated with prolonged survival in patients with ovarian cancer, recent advances in antitumor immunotherapeutic approaches rarely induce objective responses in these women. These outcomes reflect an incomplete understanding of the unique immunobiology of the ovarian tumor microenvironment (TME). Emerging evidence from our laboratory indicates that cancer cell-intrinsic dysfunction of mitochondrial stress response dramatically impairs the progression of ovarian cancer through provoking elevated antitumor immune responses. Mitochondrial fidelity is tightly linked to overall cellular homeostasis. The hostile nature of the ovarian TME, where cells encounter conditions of hypoxia, nutrient deprivation, and elevated oxidative stress, drive mitochondrial dysfunction. Such mitochondrial stress triggers adaptive responses to restore mitochondrial homeostasis, which facilitates malignant progression. Further understanding the cellular response to mitochondrial stress in ovarian cancer may be particularly important, as our laboratory has identified a germline encoded nonsynonymous single nucleotide polymorphism in the gene BLTP3A (found in ~18% of the population and predicted to generate a loss-of-function phenotype) that is associated with dramatically improved survival for high-grade serous ovarian cancer (HGSOC) patients. While the role BLTP3A in cancer remains elusive, preliminary research by our laboratory has revealed that BLTP3A promotes mitochondrial homeostasis through facilitating mitophagy in HGSOC. Specifically, BLTP3A promotes tethering of lysosomes with autophagosomes to drive the elimination of damaged mitochondria. However, dysfunctional BLTP3A promotes damaged mitochondrial accumulation - this generates inflammatory responses through cGAS/STING and elicits elevated orchestration of cellular antitumor immune responses through type I interferon activity. In fact, our new data show that HGSOC specimens expressing polymorphic M1098T BLTP3A demonstrate elevated numbers of effector T cells in these tumor beds. This was observed in association with the emergence of a distinct type I interferon signature in these tumors: likely driven by active cGAS/STING signaling. Additionally, we have clarified that BLTP3A functions as a mitochondrial stress response molecule by associating with autophagic machinery to regulate the turnover of damaged mitochondria though mitophagy. Here, we will utilize our unique mouse models, reagents, and our extensive ovarian tumor bank to further characterize the biology of BTLP3A and its impact on the orchestration of protective immunity in ovarian cancer.

NIH Research Projects · FY 2026 · 2024-12

ABSTRACT Seven well-established oncoviruses collectively contribute to approximately 12% of all human cancers. Chronic infection with the hepatitis B virus (HBV) alone is responsible for approximately 360,000 liver cancer cases per year worldwide. Unlike human papillomavirus (HPV), which promotes tumorigenesis through the provision of E6 and E7 oncogenes, the mechanisms underlying HBV-driven carcinogenesis remain incompletely understood. The integration of HBV sequences into the host genome is widely observed in HBV positive tumors, suggesting its oncogenic role. It is hypothesized that HBV integrations may directly alter the protein sequence or expression level of nearby genes and increase genome instability. We conducted long-read sequencing on HBV-positive tumors and cell lines to fully map HBV integrations. Surprisingly, we identified HBV integration-bridged chromosomal translocation events in all analyzed samples, indicating their frequent occurrence in HBV- positive tumors. These chromosomal structural variations may facilitate enhancer hijacking, bringing strong enhancers into proximity with oncogenes located in different chromosomes or topologically associating domains (TADs). Enhancer hijacking has been widely implicated in human cancer, but has not been connected to oncoviral integration. We propose that HBV integration-bridged chromosomal translocations lead to enhancer hijacking, contributing to the tumorigenesis of HBV-positive tumors. To test this hypothesis, we performed high-throughput chromosome conformation capture (HiC) on Tong and SNU761 cell lines to profile genome-wide DNA-DNA interactions. Our analysis revealed neo-TADs across HBV integration-bridged chromosomal translocations, affecting key cancer genes such as NRAS and ST3GAL1. In this study, we aim to validate these enhancer-hijacking events (Aim 1) and identify additional events in other cell lines (Aim 2). Our findings will unveil a novel mechanism of oncovirus-induced tumorigenesis. Furthermore, considering that agents disrupting enhancer function, such as BET and CDK inhibitors, have shown promising results in clinical trials for various cancers, our study may nominate these enhancer-targeting drugs for liver cancer treatment.

NIH Research Projects · FY 2026 · 2024-11

Project Summary/Abstract Women have been underrepresented in neuroimaging studies of opioid use disorder (OUD) and even fewer neuroimaging studies have targeted female-specific health factors, such as the menstrual cycle. This is concerning because women have disproportionately higher rates of relapse and treatment drop out, and cycling levels of estrogen are known to impact drug-craving, with hormone levels around ovulation potentially increasing vulnerability of relapse, though the neural mechanism leading to this result is unclear. Recent preclinical work has shown a clear interaction between ovarian hormone changes, dopamine-dependent circuitry, and sensitivity to reward cues and addictive substances. Parallel data in healthy women shows an uptick in subjects’ propensity for risk-taking, a dopamine sensitive neurocognitive process, surrounding ovulation, the phase of the menstrual cycle when estrogen is the highest. This suggests dopamine modulation of substance-use related behavior during this time, but longitudinal studies examining dopamine-dependent behaviors in parallel with the menstrual cycle in women with OUD remain lacking. To address this, I will conduct a serial and longitudinal fMRI study of risky decision-making in women with OUD and comparison controls across a full menstrual cycle (8 sessions/person). Computational modeling will be used to quantify risk-taking propensity through known-risk tolerance (a person-specific parameter of risk-taking propensity when the probability of reward is known) and ambiguity tolerance (a separable mechanism when the exact probability of reward is unknown). Previous work in my laboratory has found ambiguity tolerance to be a more state-sensitive measure, finding its fluctuation is predictive of opioid reuse, and thus a focus of this study. Aim 1 will identify the relationship between intra- individual changes in cycling hormone levels (estrogen and progesterone) and risk-taking (through known-risk and ambiguity tolerance), hypothesizing an increase in ambiguity tolerance during ovulation. Success of this aim could provide potential behavioral risk markers for drug-reuse in women with OUD informing sex-specific interventions. Aim 2 will assess the relationship between menstrual cycle phases and changing neural signatures of the subjective value of risky and ambiguous options, based on person- and session-specific trial-by-trial valuation based on computational risk-taking propensity. As neural signals of subjective value are dopamine- dependent, increased sensitivity, as hypothesized, in canonical value regions (e.g. ventral striatum) surrounding ovulation may be indicative of stronger dopamine modulation during this time. Thus, this research will identify underlying hormonal and neural mechanisms contributing to sex differences in clinical features of OUD. By completing the proposed research aims, training goals, and experiential learning activities, I will gain training in neuroeconomic theory, advanced neuroimaging methods, and clinical translation that is key to my development as an independent researcher looking to contribute to advancing of psychiatric treatment and diagnosis.