Columbia University Health Sciences

NIH Research Projects · FY 2026 · 2026-05

Mental health (MH) disorders affect over 970 and 59.3 million people worldwide and the U.S, respectively, and remain the leading cause of disease burden across the lifespan, driving significant disability, premature mortality, and elevated risk for comorbid physical health conditions and a staggering national economic impact. Despite decades of research, the burden has not measurably decreased since 1990. In the U.S., nearly half of individuals with mental illness and over 70% with substance use disorders do not receive adequate care. Structural obstacles—including workforce shortages, high costs, negative attitudes, and fragmented care systems—continue to impede access. Implementation Science (IS) offers vital evidence-based approaches to close the persistent gap between evidence-based MH research and routine practice, yet few proven interventions have been scaled successfully to benefit large populations. The IMPACT-MH T32 Training Program (Implementation Science and Partnerships Advancing Care and Training in Mental Health) seeks to cultivate the next generation of MH IS researchers committed to sustainably reducing the U.S. treatment gap. Postdoctoral fellows will engage in intensive mentorship and a fully integrated curriculum spanning all research phases: pre-intervention design, intervention delivery, and post-implementation evaluation. Early emphasis on sustainability and partnerships with communities and policymakers will inform design choices—ensuring that interventions can be effectively delivered, scaled up, and rigorously evaluated over time. Training domains include deployment-focused research—contextual adaptation and stakeholder co-design of evidence-based interventions (EBI) across varied settings—and dissemination, implementation, scale-up, and policy research aimed at securing sustainable MH services. Through tailored mentorship and collaborative training with faculty experts in public health, psychology/psychiatry, IS, and health policy, fellows will develop the interdisciplinary perspectives and the conceptual, methodological, and technological competencies necessary to advance MH IS research. Mentored by experienced faculty, a cohort of four fellows, appointed for two to three years, will partner with communities and policymakers to design projects and pursue competitive NIH awards (including K-series and R-series proposals) will enhance the relevance, feasibility, and impact of their research. Leveraging well-established multisectoral partnerships with community service organizations, health networks, faith-based coalitions, and government programs, IMPACT-MH T32 ensures that fellows’ research informs real-world services and policy. Graduates of IMPACT-MH will be equipped to translate emerging discoveries into sustainable, evidence-informed mental health care systems and policies that strengthen the public health impact of NIMH-supported research (NIMH objective). By training leaders, fostering cross-disciplinary collaboration, building multi-sector partnerships, tailoring and scaling EBI, and advancing sustainable solutions, this program will make significant strides toward closing the U.S. mental health treatment and research gap.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Intestinal failure (IF) occurs when patients are not able to maintain sufficient hydration or nutrition through oral intake alone due to either inadequate length of bowel (“short gut syndrome”) or inadequate function of the bowel. Intestinal transplantation (ITx) is the definitive therapy for patients with IF who have no possibility of enteral independence and the only remaining therapy once parenteral nutrition fails, but its use is limited by high rates of rejection that necessitate increased levels of immunosuppression, predisposing patients to infections, malignancy, and graft-versus-host disease. Therefore, identifying strategies to avoid ITx rejection, especially by developing donor-specific tolerance in an otherwise immunocompetent host, would make ITx a more attractive therapeutic option for patients with IF and might also be a useful strategy for other types of transplantation. Based on our pre-clinical studies, matching donor/recipient major histocompatibility complex (MHC) class II appears to be a promising strategy. We developed a swine orthotopic ITx model based on our clinical ITx protocol and found that, unlike fully-MHC-mismatched pairs, sharing only a portion of a single class II allele decreased rejection and promoted the development of regulatory T cells (Tregs) and donor-specific hyporesponsiveness in the graft, while greater MHC sharing extended these findings to the peripheral blood and permitted durable mixed chimerism (donor cells in the recipient’s blood) in a small pilot experiment cohort. We therefore hypothesize that selectively matching donor/recipient MHC class II, which is not currently performed routinely, promotes longer rejection-free survival (RFS) of ITx grafts by minimizing rejection through expansion of Tregs, possibly in a dose-dependent fashion. If our hypothesis is validated, class II sharing could be used to improve ITx outcomes since living donors are usually first-degree relatives and share at least half of their class II alleles with the recipient, and it is also feasible to achieve class II sharing in deceased donor transplantation because some class II alleles exist at high frequency in the general population. Based on our in vitro data, we additionally hypothesize that the mechanism by which class II sharing promotes regulatory tolerance is through linked suppression. If supported by our data, this too would present an opportunity since this immunological principle could be applicable to all forms of transplantation, not just ITx. Therefore, the overall goal of this project is to test our hypothesis regarding the clinical advantages of class II sharing and to evaluate the immunological mechanism by which this occurs. Thousands of patients would benefit from ITx if outcomes were improved, and our prior data have generated a hypothesis for improving immunological outcomes. These data support pursuing further investigation, which we are uniquely poised to perform due to our novel human and large animal models and our ability to perform the proposed mechanistic analysis. Our prior human and swine studies demonstrate the feasibility of our proposed Aims.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Nationally, 6.9 million Americans ages 65 and older live with Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD). These Persons Living with Dementia (PLWD), have higher rates of unnecessary hospitalizations and emergency department (ED) visits than those without AD/ADRD. This gap in acute care utilization is more pronounced for PLWD in at-risk groups (i.e. low-income, rural, racial and ethnic groups). Primary care can improve outcomes, but physician shortages remain a barrier. Nurse practitioners (NPs), the fastest-growing primary care workforce, are key to the care of PLWD. The NP primary care model emphasizes patient-centeredness, care coordination, and social needs screening—beneficial features in the care of PLWD. NP primary care models for PLWD include NPs serving as main primary care providers (PCPs) delivering comprehensive primary care or NPs serving as ancillary PCPs providing discrete services (e.g., care coordination) to PLWD. The NP primary care models are largely invisible in administrative datasets, such as Medicare claims, because up to half of all NP care is billed incident-to a physician. In addition, primary care NPs are not distinguishable from specialty NPs because NPs lack specialty identifiers in claims. Our novel study applies new approaches, correcting for incident-to billing and the Primary Care Provider Identification Algorithm (PCP-IA), to uncover the NP primary care model in claims and examine its impact on health disparities among PLWD. The specific aims are: Aim 1. Identify PLWD receiving care in NP primary care models (i.e., NPs as main PCPs; NPs as ancillary PCPs) and assess for differences in the sociodemographic and racial and ethnic composition of PLWD across the models. Aim 2. Determine the effect of the NP primary care models on outcomes (i.e., all-cause and preventable hospitalizations and ED visits) of PLWD and evaluate which model moderates the racial and ethnic disparities in these outcomes. Using 2023 data for all Medicare beneficiaries, we will correct for incident-to-billing and apply our innovative PCP-IA to first identify primary care NPs. The PCP-IA applies 3 indicators to uncover the care model: 1) breadth of diagnoses managed, 2) predominant setting, and 3) extent of procedural care. We will then identify PLWD receiving care in two NP primary care models (i.e., NPs as main or ancillary PCPs) and show the differences in the racial and ethnic composition of PLWD receiving care across the models. With multilevel models, we will assess which NP primary care model is most effective in reducing racial and ethnic disparities in the health outcomes of PLWD. This application is responsive to the National Institute of Aging’s Research on Current Topics in Alzheimer's Disease and Its Related Dementias (PAR-25-331). As a priority of this mechanism, we leverage national data on all older adults with AD/ADRD in the US to produce foundational evidence for large-scale studies of NP care models that improve outcomes for PLWD.

NIH Research Projects · FY 2026 · 2026-05

SUMMARY Severe insulin resistance syndromes, including Donohue and Rabson-Mendenhall syndromes, are rare, life- threatening disorders caused by mutations in the insulin receptor (IR) that impair insulin binding and receptor activation. There are currently no FDA-approved therapies that directly target the receptor defect, and existing interventions provide only limited, short-term benefit. This proposal aims to address this urgent unmet need in rare disease therapeutics by advancing RF-409, a first- in-class, synthetic IR agonist. RF-409 was developed using structure-guided computational protein design to engage both insulin-binding sites (site-1 and site-2) and induce conformational changes that stabilize the IR in its active state. RF-409 exhibits high affinity and specificity for IR, activates both metabolic and mitogenic signaling pathways, and demonstrates strong thermostability and bioactivity in vivo. Preclinical studies show that RF-409 lowers blood glucose more efficiently and with longer duration than insulin in wild-type, type 1 diabetic (Streptozotocin-induced), and high-fat diet–induced obese mouse models. Notably, RF-409 is also effective in activating IR mutants that are unresponsive to insulin. To enable rigorous efficacy testing, we developed a validated knock-in mouse model (IR-D707A) carrying a patient-derived, insulin-binding–defective mutation. These mice exhibit neonatal lethality and severe insulin resistance, closely mirroring human severe insulin resistance phenotypes. RF-409, but not insulin, activates IR in this mouse model, providing a robust, disease-relevant platform for therapeutic evaluation. Aim 1 will characterize the pharmacokinetic and pharmacodynamic profile of RF-409 in wild-type, diabetic, and conditional IR-D707A mice. Time-resolved LC-MS analysis will be used to define systemic exposure and tissue distribution. Glucose-lowering efficacy and downstream IR signaling will be measured to establish PK/PD relationships and guide dose selection. Aim 2 will assess the physiological and therapeutic impact of RF-409 in the IR-D707A mouse model. We will evaluate metabolic, mitogenic, and survival outcomes following chronic administration in both adult and neonatal animals to determine therapeutic benefit in a rare disease model. RF-409 is well-characterized, highly specific, and production-ready. Its activity in both preclinical and disease- specific models support its potential as a therapeutic for rare insulin receptoropathies. Completion of this project will generate critical efficacy and mechanistic data to support IND-enabling development and may lay the foundation for a new class of targeted therapies for receptor-level metabolic diseases.

NIH Research Projects · FY 2026 · 2026-05

Changes in metabolic states require the rapid and synergistic interaction between the brain and periphery to maintain homeostasis. Circulating factors such as nutrients play fundamental roles in these processes. Hunger and satiety are controlled by food intake and related hormonal and metabolic adaptations. After a meal, an important signal that has been attributed to drive satiety is glucose, which activates the anorexigenic pro- opiomelanocortin (POMC) neurons in the hypothalamus. Interestingly, only a subpopulation of POMC neurons shows activation by increased levels of glucose. In addition to glucose, lactate, the circulating redox indicator and glucose metabolite, has been shown to affect POMC activity. Indeed, lactate derived either from the circulation or locally by glial cells has been shown to regulate neuronal function, including that of POMC neurons, thus modulating peripheral glucose metabolism as well as feeding. Changes in circulating lactate levels occur in response to feeding, when glucose levels are elevated, and fasting when glucose levels decrease. While administration of lactate has been shown to affect feeding and metabolism via the hypothalamus and POMC neurons, the mechanism(s) via which this process plays a role in physiological control of whole-body energy metabolism in association with glucose is ill-defined. We have recently shown that lactate levels in the circulation and in the cerebrospinal fluid are elevated in fed state and addition of lactate to glucose activates the majority of POMC neurons while increasing cytosolic NADH generation, mitochondrial respiration and extracellular pyruvate levels. Inhibition of lactate dehydrogenases diminishes mitochondrial respiration, NADH production, and POMC neuronal activity. However, inhibition of the mitochondrial pyruvate carrier has no effect. In support of this, MPC deletion in POMC neurons does not alter metabolism. Furthermore, our preliminary metabolic tracing data clearly showed that pyruvate derives predominantly from lactate and that similarly to lactate fatty acids induced increased mitochondrial respiration. Thus, we hypothesize that satiety promotion by POMC neurons require parallel processing of glucose, lactate, and fatty acids. During positive energy balance, glucose in POMC neurons undergo glycolysis thus generating ATP. ATP will then close the KATP channels inducing depolarization and initial activation of POMC neurons. As the ADP:ATP ratio increases, it will drive mitochondrial function which will be supported by lactate oxidation and, thus, generation of NADH to drive the ETC, and by fatty acids oxidation (in addition to lactate) to further drive the TCA cycle. We will determine the role of cytoplasmic (Aim 1) and mitochondrial (Aim 2) redox state in the regulation of POMC neuronal function and associated metabolic adaptations. In Aim 3 we will determine a) the role of fatty acids oxidation in POMC neurons and b) whether glucose, lactate and fatty acids synergistically or uniquely affect POMC neurons. The proposed studies are a logical extension of our preliminary data, and their completion will unmask a fundamental mechanistic principle in the central regulation of metabolism.

NIH Research Projects · FY 2026 · 2026-05

Abstract Discogenic back pain, is a leading cause of disability, and involves degenerative changes of the intervertebral disc (IVD), including extracellular matrix (ECM) degradation, macrophage (Mɸ) infiltration, inflammation, and pathological nerve ingrowth. Since only a small subset of patients responds favorably to conventional treatments which address the symptoms but not the disease, there is a need for new therapies to treat disc degeneration (DD). Despite the extensive association between disc inflammation and DD, the mechanisms by which inflammatory factors drive DD in the disc are unclear. The goal of this proposal is to identify the role of monocyte- derived Mɸ on the cascade of painful DD, and to determine the contributions of CCL2/CCR2 signaling on Mɸ migration into the IVD. We hypothesize that inflammatory DD promotes increases in IVD levels of the chemokine CCL2/MCP1 that acts as a chemoattractant to CCR2+ monocyte-derived Mɸ, which degrade the ECM and promote a chronic inflammatory milieu over time. In Aim 1, we will identify the dynamics in which monocyte- derived Mɸ promote a chronic inflammatory, painful degenerate IVD. We have developed an in vivo mouse model of disc inflammation using inducible activation of NF-κB in the disc, which will be used. In Aim 2, we will determine the role of CCL2 in Mɸ migration into the IVD. In Aim 3, we will investigate the efficacy of sustained intradiscal delivery of a CCL2 neutralizing antibody during disease progression in a rat IVD injury model. Successful completion of this proposal will demonstrate that CCL2 secretion by IVD cells promotes recruitment of Mɸ, loss of IVD ECM leading to discogenic pain. Depletion of circulating Mɸ and deficiency in CCL2 signaling at the ‘right time’ will identify novel therapeutic mechanisms for painful DD.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY The DNA damage response (DDR) is a cellular network that safeguards genomic stability. When compromised, genomic DNA can accumulate in the cytoplasm, triggering innate immune signaling events culminating in the expression of interferon (IFN) and IFN-stimulated genes. While IFN signaling can increase immune responses towards genomically unstable tumor cells by facilitating tumor antigen presentation and promoting the recruitment of cytotoxic T cells that mediate tumor rejection, it can simultaneously favor tumor immune evasion through the expression of PD-L1, an immune checkpoint protein that interacts with the PD-1 receptor on cytotoxic T cells, inhibiting their ability to kill cancer cells. Immune checkpoint blockade (ICB) therapies, which disrupt the interaction between PD-L1 and PD-1, have shown remarkable efficacy in reactivating T cells and eliciting robust anti-tumor responses . However, at present, only a small fraction of patients gain the full benefit of these treatments due to resistance mechanisms acquired by tumor cells. Given the complex interplay between the DDR, IFN signaling and the PD-L1-dependent immune checkpoint, elucidating these intricate relationships is crucial for developing more potent cancer immunotherapies. In preliminary work, we have conducted genetic screens to identify factors that regulate both innate immune signaling and PD-L1 levels in cancer cells. This work uncovered the SNF2-family DNA translocase SMARCAL1 as a DDR factor that favors tumor immune evasion by a dual mechanism that involves both the suppression of innate immune signaling and the induction of PD-L1-mediated immune checkpoint responses. The main goals of this proposal are to elucidate the molecular mechanisms by which SMARCAL1 suppresses anti-tumor immune responses and identify other DDR factors that function analogously to SMARCAL1. In particular, we propose 1) To define the mechanisms by which SMARCAL1 suppresses innate immune signaling in cancer cells; 2) To define the mechanisms by which SMARCAL1 regulates PD-L1 expression in cancer cells; 3) To characterize novel DDR factors that suppress innate immunity and promote PD-L1 expression in cancer cells. Our approach will utilize a combination of cellular, molecular and biochemical assays, high-throughput genetic screens, and studies in animal models. We expect that this work will offer new insights into potential targets that could be exploited for improving the efficacy of cancer immunotherapies.

NIH Research Projects · FY 2026 · 2026-05

“The Adaptation and Evolution of Resistance to Pan-RAS Inhibition in Pancreatic Ductal Adenocarcinoma” Abstract: Pancreatic ductal adenocarcinoma (PDAC) kills over 52,000 people annually in the United States. The current standard therapies are chemotherapy cocktails that provide modest survival benefits along with significant side effects. For 30 years, we have known that the vast majority of PDAC cases (~94%) are driven by activating mutations in the KRAS protooncogene, but until recently, this knowledge could not be leveraged for therapeutic benefit. The recent development of drugs that selectively inhibit specific mutant variants of KRAS (including KRASG12C and KRASG12D) have demonstrated the benefit of targeting KRAS. However, these agents only work in a subset of patients whose tumors harbor these specific alleles. Furthermore, recurrence can happen rapidly as tumors can develop alternative RAS mutations that circumvent these drugs’ function. Recently, we led a large consortium in describing the preclinical performance of RMC-7977, a novel pan- RAS inhibitor that effectively inhibits the active (GTP-bound) forms of mutant and wild type KRAS, NRAS, and HRAS. Remarkably, we found that this agent was well tolerated in mice. Across multiple classes of preclinical models, RMC-7977 exhibited strong anticancer activity, and yielded the longest extension of overall survival in the (highly chemo-refractory) KPC mouse model that has been reported to date. When tumors eventually did recur, they frequently exhibited focal Myc copy number gains, providing a means to activate the downstream mitogenic programs of RAS. The investigational analog of this agent, RMC-6236, is now in Phase 3 trials after demonstrating tolerability and showing remarkable responses in the Phase 1 setting. Here, we propose to study the development of resistance to pan-RAS inhibition in PDAC. Building from our previous work, we will utilize samples from mouse- and human derived model systems as well as human clinical trial samples to understand the evolution of genetic resistance mechanisms in response to RAS inhibition. Studies will focus on how these alterations impact tumor biology and what new therapeutic vulnerabilities they may confer. In addition, we will study how short-term adaptation allows tumors to survive pan-RAS inhibition long enough to evolve genetic resistance. We found that within days of treatment, the heterogeneity of KPC mouse pancreatic tumors collapses, with selective depletion of the most aggressive, poorly differentiated malignant cells. Strikingly, we also show that RAS inhibition induces the formation of primary cilia in the malignant cells of PDAC, enabling activation of pro-survival pathways including autocrine Hedgehog signaling. We will test how targeting ciliogenesis and cilia signaling pathways may potentiate RAS inhibition by overcoming early adaptive responses to treatment. The proposed experiments will combine innovative experimental techniques, advanced computational approaches, high quality model systems, human tissues, and clinical trial samples to comprehensively study the development of resistance to pan-RAS inhibitors in PDAC.

NIH Research Projects · FY 2026 · 2026-05

Genetic diseases of the immune system (GDIS) encompass a wide range of clinical manifestations—spanning infection, inflammation, autoimmunity, and cancer—and are driven by both rare and common genetic variants. GDIS cause distinct and quantifiable dysregulation of cellular signaling pathways providing exceptional opportunities to advance our biological understanding of and precision medicines for these diseases. The growing catalog of variants identified by next-generation sequencing includes many variants of uncertain significance (VUS), introducing diagnostic ambiguity and limiting the use of precision therapeutic intervention. Furthermore, there is substantial clinical phenotypic overlap of different GDIS suggesting crosstalk and convergence of dysregulated pathways. We hypothesize that scalable functional variant mapping will clarify GDIS-gene variant effects across molecular, individual, and population levels, and that phenotypic convergence across distinct GDIS will reveal therapeutic targets for precision medicine. We have established a massively parallel, high-efficiency CRISPR-base editing framework to generate and functionally map GDIS-gene variants to relevant phenotypic readouts in primary human T cells. Using Activated PI3Kδ Syndrome (APDS), caused by PIK3CD or PIK3R1 gain-of-function (GOF) variants, as a model disease, we performed forward saturation screens, identified hundreds of novel GOF and loss-of-function (LOF) variants, demonstrate their sensitivity to Leniolisib, an FDA-approved PI3Kδ inhibitor for APDS, and identify partly drug- resistant variants that responded to precision combination therapies. Through immunophenotype wide association studies (IPheWAS), we find that ADPS may be orders of magnitude more common than previously estimated. To begin testing our convergence hypothesis, we performed large-scale screens testing variants in >100 GDIS genes involved in key T cell pathways. We identified several unexpected interactions between GDIS- genes and non-canonical pathway activities, including convergence of CARD11, PI3KCD, PIK3R1 and CTLA4 variants. We validated these interactions in patient cells with corresponding variants and demonstrate that pathway crosstalk can be leveraged as a unified dependency for precision drug interventions. We now propose to: (1) comprehensively identify disease-causing variants of PIK3CD and PIK3R1 in key cell types (T and B cells) and dissect the biochemical underpinnings of partial Leniolisib-resistance, and (2) generate and functionally map GDIS-gene variants in additional genes (including in CARD11, MALT1, NFKB1 and CTLA4) and their crosstalk across key genes and T cell pathways to identify opportunities for precision therapy interventions. We will test a range of therapies, including inhibitors of PI3Kδ, mTOR, and MALT1, and agonist treatment of CTLA4 using a fusion antibody. This work will produce high-resolution functional variant maps, uncover new genotype-phenotype relationships at the molecular, patient and population level, and establish a framework for variant-driven precision medicine across the spectrum of immune diseases.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Celiac disease (CD), a disease of small intestinal inflammation, is one of the most common autoimmune diseases with estimated worldwide prevalence >1%. Beyond a lifelong gluten free diet, treatment options for CD are limited. In most cases, the antigen(s) triggering human autoimmune disease is not known, severely hampering our mechanistic understanding of how these diseases are initiated or sustained. The exception is CD. In CD, the triggering antigen is dietary gluten, which activates gluten-specific CD4+ T cells. Not only is the antigen trigger in CD known, but its exposure can be controlled, providing truly unique opportunities to study human autoimmunity. The critical question of how a CD4+ T cell response directed against dietary gluten culminates in self-tissue damage by cytotoxic CD8+ αβ and γδ T cells, which are not thought to recognize gluten themselves, remains unanswered. The current model for celiac pathogenesis posits that cytotoxic CD8+ αβ and γδ T cell activation occurs downstream of CD4+ T cell-driven inflammation. Our preliminary data inform a revised model for CD pathogenesis, which will be applicable in autoimmune diseases beyond CD. Our central hypothesis to explain CD-mediated tissue destruction is that gluten-specific CD4+ T cells and cytotoxic T-IELs activate in parallel following gluten ingestion, with the latter cell population requiring additional tissue-derived signals for full activation. A critical aspect of our model is that CD4+ and CD8+ and γδ T-IELs have different antigen specificities. To investigate these hypotheses and dissect mechanisms through which an aberrant CD4+ T cell response to gluten culminates in specific tissue damage by cytotoxic T-IELs, we propose the following Aims. Aim 1. Dissect mechanisms through which gluten modulates Natural T-IEL populations in CD. Aim 2. Dissect the role of tissue- derived factors in unleashing the cytotoxic capacity of T-IELs in CD. Successful completion of these aims will advance our mechanistic understanding of CD and autoimmunity, and could inform novel therapeutic strategies.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Cigarette smoking is a leading cause of preventable disease and death, and people with HIV (PWH) are disproportionately affected, with smoking rates three to four times higher than those in the general U.S. population. In urban centers such as New York City, approximately 45% of PWH smoke cigarettes, significantly elevating their risk of cancer, cardiovascular disease, and reduced life expectancy. While mobile health (mHealth) technologies have demonstrated potential for supporting behavior change, existing smoking cessation apps are often generic, underutilized, or not evidence-based—and few have been specifically developed or evaluated for PWH. To address this public health challenge, our team has developed the Sense2Quit App, an innovative, sensor enabled mHealth intervention designed specifically for PWH who smoke. The app, guided by the Information Systems Research (ISR) framework, uses a smartwatch equipped with machine learning models to detect smoking gestures and provide personalized behavioral support in real time. Our pilot study among 60 PWH demonstrated the app’s feasibility, high user acceptability, and strong retention despite socio-environmental challenges commonly faced by this population. This R01 project will (1) enhance the app’s technical capabilities—improving gesture detection accuracy, data transmission stability, and battery life; (2) evaluate the app’s efficacy in a fully powered randomized controlled trial (N=450) against an active control (physical activity app), with biochemically verified 7-day point prevalence abstinence at 6 months as the primary outcome; and (3) use the RE-AIM framework to assess factors affecting reach, effectiveness, and potential for large-scale implementation. Findings from this research will contribute critical knowledge to the field of digital health, strengthen the evidence base for mHealth interventions for smoking cessation, and support the development of tailored, scalable solutions to improve health outcomes among PWH. Ultimately, this project aligns with national priorities to prevent chronic disease, promote health, and advance technology-driven public health interventions.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Sexually transmitted infections (STIs) remain a significant public health challenge in the United States, disproportionately affecting adolescents and young adults aged 15–24. Comprehensive STI screening— including extra-genital and blood testing—remains underutilized, particularly in emergency departments (EDs), where over 19 million adolescents and young adults receive care annually. Barriers such as time constraints, provider discomfort, and workflow challenges contribute to missed opportunities for STI detection. Even when STI testing occurs, patients are rarely linked to ongoing sexual health services, including STI treatment completion and HIV preventive care, leading to high rates of reinfection and continued disease transmission. Innovative interventions that fit efficiently within the ED workflow and maximize appropriate STI testing are needed. Our multi-disciplinary team developed STIckER (STI ChecK in the ER), a user-informed, theory-based digital patient decision aid designed to facilitate shared decision-making and increase STI testing rates in EDs. In a randomized controlled trial, STIckER significantly increased STI testing rates, improved patient-provider communication, and enhanced ED experience ratings. However, real-world effectiveness and implementation across diverse ED settings remain unexplored. This multi-center R01 study will evaluate STIckER’s effectiveness and implementation across 13 pediatric and adult EDs using a cluster-randomized stepped wedge hybrid type 2 trial. The specific aims of the proposal are: (1) to evaluate the effectiveness of STIckER on STI testing (clinical outcomes) among adolescent and young adult ED patients in a cluster-randomized stepped wedge trial; (2) to measure implementation outcomes across ED sites among key stakeholders, and (3) to evaluate STIckER’s impact on follow-up and linkage to outpatient sexual healthcare services. By integrating scalable, digital, patient- centered approaches into routine ED workflows, STIckER has the potential to transform STI screening and improve long-term sexual health outcomes for adolescents and young adults nationwide.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/Abstract Most sensory stimuli acquire value through learning and experience. While progress has been made in deline- ating the circuits involved in sensory value-guided behaviors, the cellular and circuit mechanisms that underlie how distinct value representations are formed during learning, regulated during behavior, and modified to ac- commodate changes in cue-outcome contingencies remain unclear. Resolving these open questions is a funda- mental challenge in neuroscience and will advance our understanding of how synaptic plasticity induced by reinforcement learning is maintained, yet behaviors remain adaptive. The overarching goal of this proposal is to seek a mechanistic understanding of the circuits underlying value-guided learning and action in the mouse me- dial prefrontal cortex (mPFC), a region essential for the imposition of value on sensory stimuli to guide behavior. Using an olfactory-based appetitive classical trace conditioning task in combination with high-density electro- physiological recordings and optogenetics, I will focus on how functionally distinct yet spatially intermingled pop- ulations of neurons encoding rewarded (conditioned stimuli, CS+) and unrewarded (CS-) odors interact within the local network to drive stable yet flexible reward-seeking behaviors. I will test the hypothesis that the CS+ and CS- populations form a mutually inhibitory circuit that underlies their behaviorally-opposing roles in reward-seek- ing (Aim 1, K99). I will investigate how the existence of a CS- population may represent a circuit mechanism to permit the maintenance of prior reinforcement despite the extinction of learned behavior, thus uncovering a pre- viously unappreciated role for the CS- ensemble in reinforcement learning (Aim 2, K99). In my R00 phase, I will interrogate the mechanisms by which CS+ and CS- representations arise during learning, testing the hypothesis that distinct inputs to the mPFC drive the reinforcement of odors predicting the presence or absence of reward (Aim 3a,b). Further, I will study how the CS+ and CS- representations are updated when cue-outcome contin- gencies are reversed (Aim 3c). Finally, I will model the mPFC circuit to reveal fundamental principles on value- guided learning, which will inform future experiments and also extend the insights that could be gained beyond that which is feasible by experimentation (Aim 3d). This work will have broad implications for various neuropsy- chiatric conditions in which adaptive value-guided learning is disrupted, including addiction and depression. Can- didate and Career Goals. I aim to establish an independent research program investigating the neural basis by which value representations are generated and flexibly regulated to support context-dependent behaviors. I have extensive experience in molecular and systems neuroscience and have developed foundational tools and in- sights for studying value learning. Career Development Plan. I will be trained by my mentors Drs. Richard Axel and Larry Abbott. Dr. Axel is a foremost leader in sensory neuroscience, who will guide me on all aspects of experimental design. Dr. Abbott is a world-renowned theorist who will provide training in the analysis and mod- eling of complex datasets. All mentors will provide career development training for my transition to independence.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY / ABSTRACT: Rationale: SARS-CoV-2 evolution has led to the emergence of viral variants that evade existing immunity in the human population, which continue to pose a threat to global public health. It has proven challenging to predict which mutations will arise in future dominant viral variants, and, as a result, it is difficult to design vaccines that provide adequate protection against viruses that will circulate in future waves of infections. Our preliminary data show that viral variant evolution is most closely correlated with evasion of serum neutralizing antibodies, and that serum neutralizing antibody responses are shaped by immune imprinting to the ancestral D614G strain. This mentored career project aims to leverage these observations to develop an in vitro model for predicting where mutations will appear in the virus and to use that information to design updated vaccines. Candidate: As a Transfusion Medicine fellow with a PhD in Genomics and Computational Biology and two years of experience in virology and immunology research, I bring a unique complement of perspectives and skills to the analysis of viral and antigenic evolution and to vaccine design strategies. Further training in advanced BSL-2-compatible pseudovirus culture, mouse immunization, and computational structural biology will be central to the completion of the proposed project and to my development as an independent physician-scientist aiming to improve our understanding and mitigation of pathogen evolution. My primary mentor, Dr. David Ho, an international leader in virology, and my complementary multidisciplinary advisory team, will ensure my research and career development progress. Environment: The Ho laboratory at the Columbia University Irving Medical Center (CUIMC) is a world leader in the study of pandemic viruses, including SARS-CoV-2, with expertise in the characterization of viral variants and serum antibody analysis. The Ho lab has access to abundant resources and many collaborators, including leaders in pseudovirus construction, structural biology, and vaccine design. CUIMC also has a long track record of supporting junior physician-scientists on their paths to successful independent careers in academic medicine. Approach: We will test the central hypothesis that widespread early exposure to ancestral SARS-CoV-2 shapes the evolutionary trajectory of the virus and that such a trajectory can be modeled in vitro. In Aim 1 we will assess the impact of mouse serum neutralizing antibodies elicited by different immunization histories on mutational profiles in cultured BSL-2-rated pseudoviruses and correlate mutations with historical public health databases. In Aim 2, we will identify whether particular epitopes on the spike protein are particularly susceptible to the emergence of mutations under serum antibody selective pressure. In Aim 3, we will design and test novel COVID-19 vaccine candidates in mice based on observed mutations that arise in pseudoviruses. This project will enhance our understanding of SARS-CoV-2, provide a framework for in vitro modeling of antigenically variable pathogens, and contribute to vaccine design strategies.

NIH Research Projects · FY 2026 · 2026-04

Project summary/Abstract Hematopoiesis is a highly regulated process fueled by hematopoietic stem cells (HSCs) and progenitors in response to physiological and pathological changes throughout life. During development, the system quickly expands to provide increasing numbers of blood cells for the growing tissues and organs. In regeneration, HSCs re-establish the hematopoietic hierarchy and supply lost blood cells to restore tissue function. In pathological conditions, dysregulated hematopoiesis drives disease progression. A detailed cellular and molecular understanding of the mechanisms of dynamic hematopoiesis is key to intervening in these processes for therapeutic benefits. Although the niche critically regulates HSCs and hematopoiesis, how the niche is dynamically regulated to adapt to the distinct demands in the ever-changing conditions is not clear. Our previous work has identified key cellular components of the niche in the bone marrow and developing liver, allowing precise studies of niche dynamics in these organs. Our recent work has also revealed surprising cell fate plasticity in the bone marrow niche. The proposed work in this application builds on these findings to 1) define niche dynamics and plasticity in development, regeneration, and hematological disease, 2) uncover the mechanisms that regulate these processes, and 3) harness the mechanisms to enhance niche function and boost blood cell production. We will use several novel mouse models generated in the lab to study the function of key pathways in regulating niche dynamics and cell fate plasticity. We will employ single-cell transcriptomics, imaging, metabolic analysis, functional studies, and other cutting-edge approaches to understand how these key pathways regulate niche dynamics and plasticity. Collectively, these experiments will uncover novel mechanisms that regulate niche cell dynamics and plasticity with broad implications for better treatment of blood diseases. They may lead to transformative strategies for boosting blood cell production by enhancing niche function.

NIH Research Projects · FY 2026 · 2026-04

PROJECT ABSTRACT Long-acting injectable (LAI) pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) represent a promising but underutilized class of HIV medications that can significantly benefit patients who struggle with oral medication adherence. Despite their potential, LAIs face substantial implementation barriers due to their logistical complexity compared to traditional oral medications. While high-volume LAI delivery is currently rare across U.S. HIV clinics, clinical decision support (CDS) systems offer a potential solution for efficiently scaling LAI programs. This project addresses the critical need for infrastructural support in LAI delivery by developing and evaluating a comprehensive Resource Package to accelerate the adoption of LAI-specific CDS in HIV clinics nationwide. We hypothesize that providing clinics with a standardized Resource Package will lead to more efficient workflows, improved care coordination, enhanced patient outcomes, and sustainable LAI program growth. The Resource Package will include: (1) a compendium of LAI-specific CDS tool options with implementation guidance, (2) decision-making worksheets for CDS design, (3) low-fidelity prototypes with adaptable wireframes, (4) build checklists for tool development, and (5) evaluation metrics for assessing CDS tools. Our project has three specific aims. First, we will identify promising CDS tools and processes through synthesis of practices at 10 Clinical Partner Sites currently delivering LAIs at high volume. Second, we will co-create the Resource Package through five multi-disciplinary working groups, each including clinicians, CDS end-users, builders, and implementation scientists. Third, we will assess the Resource Package's impact on clinics' readiness to build LAI CDS tools and their progress in the build process through pre-post surveys and in-depth qualitative analysis. The project will be carried out by an interdisciplinary team including implementation scientists, clinicians, and CDS specialists, working collaboratively with 10 Clinical Partner Sites, two national dissemination partners, and a Community Advisory Board. This research directly responds to NIMH priorities (PAR-22-060 and NOT-MH-23-275) by developing a systematic intervention to promote organizational readiness and capacity for implementing LAIs with fidelity and effectiveness. By establishing a standardized approach to CDS development for LAIs, this project aims to overcome a significant barrier to widespread LAI implementation, ultimately expanding access to these valuable HIV prevention and treatment options for vulnerable populations currently underserved by conventional oral medication approaches.

NIH Research Projects · FY 2026 · 2026-04

Computational and experimental approaches to decode domain-specific protein-RNA interactions Project Summary RNA-binding proteins (RBPs) play central roles in post-transcriptional gene regulation by diversifying the types and levels of protein products expressed in specific cellular contexts. This is achieved through interactions of RBPs with specific sequence or structural elements in their target transcripts. Disruption of these regulatory elements accounts for a substantial fraction of human disease associations. However, since most of these elements are embedded in the noncoding genomic regions, they are currently annotated poorly in the human genome. While CLIP-seq and its many variants can map RBP binding footprints on a genome-wide scale, such maps remain sparse in coverage concerning both the number of RBPs and cell types. Predictive computational models can potentially complement experimental data and provide powerful tools to interpret the functional impact of genetic variants, but the success of this approach is still limited. We realize that a major challenge in the precise mapping and prediction of protein-RNA interactions is a critical lack of technologies that can delineate the specificity of individual RNA-binding domains (RBDs) of multi-domain RBPs, which account for about half of all RBPs in humans. Since the current CLIP methods pull down all RNA fragments crosslinked to any RBDs in a mixed population, with each individual RBD recognizing short and degenerate motif sites, we are unable to deconvolute the binding sites of individual RBDs. Such resolution is required to precisely understand the mechanisms conferring the specificity of protein-RNA interactions and interpret the functional significance of genetic variants. In this study, we propose two complementary strategies to overcome the fundamental challenge and develop new methods that will enable one to map domain-specific protein-RNA interactions in the native cellular context, at single-nucleotide resolution, on a genome-wide scale. This project builds on the tight integration of complementary expertise of the Zhang lab in RNA and computational biology and Wang lab in chemical biology. If successful, this study will produce platform technologies that will find impactful applications in studies of gene expression regulation, genotype-phenotype relationships, and development of RNA-based precision genetic medicine.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT This research proposal is in response to the NOT-OD-24-079 “Notice of Special Interest: Women’s Health Research” focused on health conditions that are female-specific. The ovary is the first organ to age in the human body. Ovarian aging negatively influences lifespan and a broad range of health outcomes in cardiovascular, skeletal, metabolic, immune, and neurocognitive systems in women. Despite these broad impacts, ovarian aging has received limited scientific attention. The biological mechanisms that drive ovarian aging, and how they influence broader healthspan in women, remain poorly understood. The objective of this proposal is to investigate the molecular mechanisms by which NBR2, a long non-coding RNA, contributes to the remarkably complex processes of ovarian aging. By performing genome wide association studies (GWAS) of two reproductive aging- related traits, age of natural menopause (ANM) and reproductive lifespan (RL), we found that genetic variants within a gene-rich haplotype block at the BRCA1 locus are associated with both traits. Our integrative post- GWAS analysis, combined with functional genomic studies in human ovarian cell models, identified a causal non-coding regulatory variant (rs2298862 T>C) associated with both later ANM and longer RL. Although previous ANM GWAS studies identified BRCA1 as the causal gene at this locus, our functional genomic studies experimentally validated that NBR2 at the true target gene. The variant downregulated NBR2 expression, suggesting that NBR2 is a likely driver of the reproductive longevity phenotypes. The major goal of this project is to uncover the mechanisms by which NBR2 modulates female reproductive longevity (Aim 1) and elucidate the mechanisms by which the causal regulatory variant regulates NBR2 expression in diverse ovarian cell types (Aim 2). In Aim 1, I will test the hypothesis that reduced NBR2 expression delays ovarian aging by modulating pro-longevity signaling pathways. I will generate CRISPR/Cas9-mediated knockout NBR2 cell models and perform unbiased RNA-immunoprecipitation followed by mass spectrometry to identify NBR2 interactors and downstream targets. In Aim 2, I will test the hypothesis that the rs2298862 (T>C) variant reduces NBR2 expression by altering long-range chromatin interactions, disrupting transcription factor binding, and modulating enhancer activity. I will generate multiple ovarian cell types from CRISPR-engineered human embryonic stem cells carrying the variant and assess its impact on NBR2 expression, chromatin architecture, transcription factor (TF) binding, and aging-related cellular phenotypes. By identifying pathways and regulatory mechanisms by which NBR2 and its downstream regulators influence ovarian aging, this project will provide a molecular framework for understanding human reproductive longevity and may reveal targets for preserving ovarian function and healthspan in women.

NIH Research Projects · FY 2026 · 2026-04

Measles (MeV) causes disease worldwide despite efforts towards eradication by vaccine, primarily because it is readily spread between people. Acute MeV infection causes immune amnesia, increasing susceptibility to other infectious diseases. In addition, rare but severe neurological complications can develop several years after measles due to persistent MeV infection of the central nervous system (CNS). People with impaired cellular immunity are at increased risk of developing severe measles but often cannot be vaccinated since the vaccine virus itself can lead to fatal illness in this population. There is no specific therapy for acute or persistent MeV manifestations. The only available intervention beside vaccination is hyperimmune sera from vaccinated individuals. The current vaccine elicits antibodies directed against the two envelope glycoproteins, the receptor-binding hemagglutinin and the fusion(F) protein. The antibodies against the hemagglutinin are neutralizing, while current-vaccine-elicited antibodies against the fusion protein are not. This contrasts with wild type induced immunity that elicits effective anti-F neutralizing antibodies. This indicates a clear shortcoming of the current vaccine (i.e., inability to elicit anti-F neutralizing antibodies) that affects the potency of hyperimmune sera obtained from vaccinated people. We have recently identified several anti-F neutralizing antibodies, and we propose to identify several others to build a defined cocktail of long-lasting monoclonal antibodies for future clinical application. The proposed work will address two Specific Aims: 1. Production and selection of anti-F neutralizing antibodies. 2. Evaluate the protection afforded by anti-F protein passive immunotherapy. Our application will significantly impact the growing number of severely immune- compromised individuals who cannot be vaccinated with the current live MeV vaccine and would benefit from a defined cocktail of neutralizing monoclonal antibodies.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY The β5 integrin in the form of the αvβ5 heterodimer is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and serves as a predictor of poor survival in PDAC patients. Genetically deleting β5 integrin in PDAC cells greatly delays tumor growth and metastasis in mice. Our studies over the years revealed that αvβ5 integrin expression is induced by transforming growth factor (TGF)-β released by various cells in the PDAC tissue, and that the integrin serves as a major activator of TGF-β to allow PDAC to maintain an αvβ5- and TGF-β-rich tumor microenvironment (TME). This system likely promotes the desmoplastic, hypo-perfused, immunosuppressive, and metastatic nature of the disease as TGF-β is known to be one of the key inducers of these characteristic TME features. Our recent data show that the αvβ5-binding iRGD tumor-penetrating peptide effectively inhibits the αvβ5-mediated TGF-β activation widely in the tumor. Long-term therapy with iRGD appears to reduce the malignant TME features of PDAC leading to improved perfusion, CD8+ T cell infiltration, less stromal fibers, and strikingly reduced metastasis in PDAC mice. iRGD was originally developed as a drug delivery system that acutely induces vascular and tissue permeability in the tumor to enhance tumor- specific entry and efficacy of drugs. The new findings above suggest that iRGD also chronically modifies the TME, which may contribute to its ability to deliver and potentiate various therapies. Our recent work also revealed that iRGD preferentially targets and depletes regulatory T cells (Tregs) in mouse PDAC to expand CD8+ T cells because PDAC-infiltrating Tregs express the αvβ5 integrin perhaps as an activation marker. Likely as a result of these combined effects, iRGD sensitizes PDAC to anti-programmed cell death ligand 1 (PD-L1) therapy in PDAC mice. The ongoing iLSTA clinical trial that studies the safety and preliminary efficacy of iRGD along with gemcitabine, Nab-paclitaxel, and an anti-PD-L1 antibody (durvalumab) in PDAC patients is showing promise. Here, we will characterize the effects of iRGD on the PDAC TME to maximize the benefits of using iRGD as an adjunct for other therapies. The goal is to identify master regulators (MRs) of response and resistance to iRGD therapy to develop probes that help stratify patients to iRGD therapy and novel targets that would further improve the efficacy of iRGD therapy. To this end, we will analyze the phenotypic and functional changes of various PDAC components, such as blood vessels, immune cells, fibroblasts, cancer cells, and stromal fibers in response to iRGD at gene and protein levels using spatial transcriptomics, humanized PDAC mice, and clinical samples from the iLSTA trial. MRs of response will be validated as a predictor of positive outcome in PDAC patients. Inhibitors of the MRs of resistance will be tested in proof-of-principle treatment studies in mouse models to study if they outperform or enhance the efficacy of existing regimens.

NIH Research Projects · FY 2026 · 2026-04

Summary One of the major problems in human genetics is understanding the genetic causes underlying complex phenotypes, including neuropsychiatric traits such as autism spectrum disorders, bipolar and schizophrenia. Despite tremendous work over the past few decades, it has been frustratingly difficult to get a good understanding of the underlying biological mechanisms in most cases. Nonetheless, large psychiatric genetic studies are beginning to deliver fundamental knowledge about genetic architecture, disease pathways and specific genetic loci for follow-up. Most psychiatric genetic studies to date have focused on individuals of European origin, leading to profound difference in genetic discoveries with limited transferability of results across populations, but also limiting our knowledge about disease pathophysiology in general. Recently, several large projects in neuropsychiatric genetics have focused on collecting and assembling genetic and deep phenotype data in admixed and populations of different geographic origins. Such projects include the Latin American Genomics Consortium (LAGC), the Genomics of Autism in Latino Ancestries (GALA), the Ancestral Population Network (APN), and PsycheMERGE. Most approaches for causal variant discovery fail to account for key complexities that arise in studies of varying geographic origin, including heterogeneity across populations in terms of effect sizes and linkage disequilibrium (LD) structure, and correlations across geographic origins. Furthermore, with meta-analyses with external LD from reference panels being commonly used in genome-wide association studies, certain types of inconsistencies are inevitable. Therefore, existing methods tend to have suboptimal power and can even produce invalid results, i.e., they prioritize non-causal variants. We propose to develop robust fine-mapping tools that model heterogeneity across populations and are robust to inconsistencies in the data. We also propose to leverage a possibly large number of genetically related traits available in electronic health record systems, including diagnoses, lab results and biomarkers with the goal to refine phenotypes and improve power of genetic association studies for psychiatric phenotypes. We further propose to apply these methods to the largest available collections of datasets from various geographic origins for autism, bipolar, schizophrenia and other neuropsychiatric traits, including data from several psychiatric genetics consortia and electronic health record systems. We believe that the proposed research is very timely and leverages modern datasets with the potential to substantially improve our understanding of the biological mechanisms underlying risk to neuropsychiatric diseases, including schizophrenia, autism and related disorders.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT The mammalian heart undergoes profound transcriptional and phenotypical remodeling during postnatal development, a process known as cardiac maturation. However, the molecular mechanisms driving this transition is not fully understood, posing a major challenge in cardiac regenerative medicine, where induced cardiomyocytes from pluripotent stem cell differentiation or non-myocyte reprogramming exhibit an overall immature phenotype that severely limits their application in cell therapy and in vitro disease modeling. In this K99/R00 application, I propose to integrate cutting-edge single cell multiomics with state-of-the-art computational methods to unravel the cell-type-specific gene regulatory networks governing cardiac maturation, and develop a novel dual-reporter system to model and enhance cardiac maturation in vitro and in vivo. During the K99 phase, I will characterize the epigenomic changes of the mouse heart during postnatal development at a single cell resolution using various single cell multiomic technologies (Aim 1), and construct cell-type-resolved gene regulatory networks underlying cardiac maturation using bioinformatic approaches coupled with deep learning (Aim 2). I will also establish cell culture and mouse models with CRISPR-mediated knock-in of dual-fluorescent reporters to track and assess cardiomyocyte maturation (Aim 3a). During the R00 phase, I will experimentally characterize key regulatory elements and novel transcriptional regulators using functional genomic approaches (Aim 3b). I will also leverage these findings to enhance the maturation of in vitro-derived cardiomyocytes for improved therapeutic potential (Aim 3c). The expected outcomes of my proposed research will deepen our understanding of postnatal cardiac development and uncover new therapeutic strategies to improve cardiac function after injury. My career goal is to lead an independent research group that develops and employs innovative technologies to study the regulatory mechanisms underlying cardiac development, regeneration, and disease. In my K99 phase, I will acquire crucial knowledge and skills in advanced single cell genomics and computational biology to complement my previous expertise in developmental biology and cardiac research. My career development will be supported by an exceptional mentoring and advisory committee from UCSD/Salk/HHMI, along with world-class resources, training opportunities, and institutional support at UC San Diego. These elements will provide a strong foundation for my successful transition to an independent tenure- track faculty position.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract Inflammatory Bowel Disease (SLE) is a chronic autoimmune disease characterized by severe inflammation in the intestinal tract, that is accompanied by increased intestinal permeability along with increased immune responses. To date, the exact cause of IBD remains poorly understood. In recent years, genome-wide association studies (GWAS) have been used to identify genetic risk factors for IBD. Interestingly, most single nucleotide polymorphisms (SNPs) identified through GWAS reside in non-coding regions, with many found in the regulatory elements known as long-noncoding RNAs (lncRNAs). In this application, we propose to characterize a previously uncharacterized IBD-associated lncRNA that we have named lnc15. Our preliminary studies have shown that lnc15 is downregulated in IBD patients and the IBD-associated allele of lnc15 is associated with a decrease in its expression and alterations in its secondary structure. Knockout of lnc15 in mice increases susceptibility to dextran sulfate sodium (DSS) induced colitis as well as T cell transfer colitis. Further mechanistic studies show that lnc15 post-transcriptionally regulates the level of Tbet mRNA to regulate both CD4+ T conventional (Tconv) and T regulatory (Treg) cell functions. In this R01 proposal, our central aim is to understand the role of lnc15 in development of experimental colitis in mice, thereby shedding light on IBD susceptibility in patients. We will elucidate the molecular mechanism by which lnc15 acts to affect the level of Tbet, how altered Tbet affects Tconv and Treg, and how the IBD-associated GWAS SNPs alter the structure and function of lnc15.

NIH Research Projects · FY 2026 · 2026-03

Abstract This R21 application aims to develop a novel group independent component analysis (ICA) algorithm, incorporating time-frequency information (GtfICA) to capture the temporal dynamics of functional networks (dFN) in longitudinal studies. The GrfICA will provide a comprehensive view of the spatiotemporal organization of brain activity by addressing the limitations of traditional functional connectivity methods. Our sample includes n=1000 cognitively normal participants aged 18-85 from the NKI-RS study, who were followed up to 3 years. All participants had both single- and multi-band resting-state fMRIs at each visit. We will identify age-related changes and assess the test-retest reliability of longitudinal changes in dFN between multi-band and single- band data. This is crucial for understanding the consistency and reproducibility of results across different imaging protocols that often occur in long-term longitudinal studies. In Aim 1, we will develop an independent component analysis utilizing time-frequency features and its extension to multi-subject analysis (GtfICA). We will evaluate their performance using extensive numerical experiments. Using NKI-RS baseline data, GtfICA will identify age-related changes in the dFN. We will assess the replicability of the identified age-associated dFN patterns across different fMRI acquisition sequences. In Aim 2, we will extend GtfICA to harmonize single- and multi-band longitudinal data collected longitudinally. We will incorporate the sampling rate changes in the GtfICA and quantify and test the longitudinal changes above and beyond the sequence changes. Also, we will evaluate the test-retest reliability of the longitudinal changes in dFN between multi- band and single-band data. Finally, we will evaluate the stability of the longitudinal changes in the dFN when the acquisition sequences change over time when only partial information on sequence changes is available. The outcome of this proposal is a crucial step toward accurately quantifying and testing the effect of aging and neurodegenerative disease on brain function across different image acquisition protocols and longitudinal changes. This study will enhance the generalizability of the inferences on dFN. The outcome of this proposal will be the basis for a future new R01 project. This subsequent research will evaluate longitudinal changes in the dFN in ADRD relative to aging in multiple clinical populations.

NIH Research Projects · FY 2026 · 2026-03

We propose a comprehensive, long-term program that addresses major gaps in our understanding of athero- sclerotic cardiovascular disease (CVD) and cardiometabolic disease. We explore new, disruptive concepts re- lated to the roles of the macrophage (Mφ) efferocytosis-resolution cycle in promoting a key feature of stable human atheroma, notably fibrous cap thickening. We will then integrate these concepts with an area of great interest to NHLBI, namely, the exacerbation of CVD by metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH), with a focus on common mechanisms and therapeutic targets in atherosclerosis and MASH, particularly MASH with liver fibrosis. Major gaps that will be addressed include (1) What are the earliest upstream signaling events in effero-Mφs that activate athero-relevant resolution pathways, particularly fibrous cap for- mation? (2) What is the role of effero-Mφ crosstalk with adaptive immune cells in atherosclerosis? (3) How are lesional Mφs protected from the cellular stresses of efferocytosis? (4) Do atherosclerosis and MASH share com- mon mechanisms that are amenable to integrated therapy? (5) How does MASH fibrosis drive atherosclerosis? Based on exciting new data, our atherosclerosis studies will investigate: (1) a surprising pathway that serves as the initial trigger of resolution signaling in effero-Mφs; (2) a new mechanism of crosstalk between effero-Mφs and regulatory T cells; and (3) effero-induced repair of oxidatively damaged DNA, which is relevant to clonal hema- topoiesis, a risk factor for age-related CVD. Using both hypothesis-driven and unbiased 'omic' approaches, we will carry out mechanistic studies in human Mφs; causation studies in genetically altered mice; single-cell RNA- seq and cell-tracing studies to elucidate links between Mφ effero-resolution and fibrous cap formation; and anal- yses of human atheroma. We will then apply these concepts to the integrated topic of athero-MASH, with the hypothesis that impaired effero-induced reprogramming of Mφs to a repair phenotype is a common, therapeu- tically targetable mechanism of both of these linked diseases. This idea links the lab's work on Mφ effero- resolution in atherosclerosis with exciting new work showing that efferocytosis by liver Mφs is defective in MASH and promotes MASH fibrosis. Using a unique athero-MASH model with human-relevant features, in which spe- cific blockage of liver fibrosis promotes cap thickening in athero-lesions, we will elucidate which effero-resolution programs are relevant to both atherosclerosis and MASH and explore how MASH fibrosis exacerbates athero- sclerosis. We will then test the hypothesis that restoring efferocytosis to Mφs in the athero-MASH model through genetic engineering and, by way of translation, cutting-edge "designer" Mφ and RNA therapies, will have an additive or synergistic benefit for both diseases. In summary, by focusing on a key root cause of atherosclerosis, i.e., failed Mφ-mediated effero-resolution, and by studying atherosclerosis in the context of MASH, the R35 ad- dresses major gaps relevant to CVD and cardiometabolic disease. Moreover, a major goal is to train young scientists and continue our service to the cardiovascular community, which should amplify the benefit of the R35.