New York University School Of Medicine

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY There is an urgent and crucial unmet need for tools and resources developed to understand the vascular pathophysiology of in vivo neuroimaging findings in amyloid-related imaging abnormalities (ARIA). We propose to develop and validate a comprehensive set of in vivo and ex vivo post-mortem MR imaging protocols, along with analytical tools focusing on vascular pathogenesis and pathophysiology. These resources will help link MR imaging findings with clinical symptoms, cognitive functions, plasma biomarkers, and histopathological findings in a cohort that will be longitudinally followed with both ante-mortem and post-mortem data. We have assembled a multi-disciplinary research team with leading experts in several key aspects of the proposed study to achieve the following specific aims. Specific Aim 1. Characterize the vascular pathology contributing to ARIA using advanced MRI techniques in a prospective cohort of patients developing ARIA following anti-amyloid antibody treatment, compared to controls. Utilizing multi-modal vascular imaging protocols including the widely applied MarkVCID 3T imaging protocol with high reproducibility, we will assess water permeability across a vessel wall, cerebrovascular reactivity (CVR), and cerebral blood flow (CBF) before and after anti- amyloid treatment. Additionally, free water (FW) imaging, peak width of Skeletonized Mean Diffusivity (PSMD), and cerebral oxygen metabolism will be used to assess neuronal/axonal injury associated with ARIA. Specific Aim 2. Characterize longitudinal changes of plasma biomarkers before and after ARIA is identified and correlate these changes with the imaging findings described in Aim 1 and clinical performance in patients with and without ARIA. The plasma biomarkers include markers of neurodegeneration, neuroinflammation, and vascular pathology used in studies of Alzheimer's disease (AD) and AD-related dementias (ADRD) to better understand disease mechanisms and identify ARIA risk factors. Specific Aim 3. Conduct histopathology and proteomics studies on patients with ARIA who have participated in Aims 1 and 2 as well as utilizing available post-mortem brains from other patients with ARIA, to provide mechanistic insights and potentially identify novel ARIA-associated biomarkers. Specific Aim 4. Develop in vivo and postmortem tools and resources, along with relevant biomaterials of ARIA, to be shared with the research community from the above studies. We will leverage the synergy between the current project and two other large ongoing studies, which focus on in vivo clinical biomarkers and vascular pathophysiology, alongside postmortem tools and resource development for AD/ADRD. This unique synergetic effort will greatly enhance the success of our initiatives. Together, we aim to build a comprehensive schema for capturing metadata in prospectively designed in vivo and ex vivo studies. This schema will aid in determining the cause, impact, and prognosis of ARIA, ultimately informing future clinical guidance.

NIH Research Projects · FY 2025 · 2025-06

Project Summary Remitting-relapsing inflammatory disorders affect millions of people and have no cure. Psoriasis (PsO) is a prototypic remitting-relapsing inflammatory disease that despite treatment success in promoting symptom remission, patient relapse almost always occurs. Psoriatic lesions often recur in the same location, indicative of locally encoded disease memory. Our lab and others have uncovered that epithelial stem and progenitor cells (ESPCs) can remember inflammation by epigenetic mechanisms in murine models of disease. These long-lived cells maintain chromatin accessibility to stress response genes long after inflammatory resolution. My preliminary data suggest that keratinocyte stem cells in skin from resolved psoriatic lesions have an enrichment of inflammatory transcription factors’ binding motifs in their differentially accessible regions. Additionally, my preliminary data indicate that keratinocytes capable of encoding inflammatory memory and becoming sensitized to secondary challenge have decreased binding activity of homeostatic transcription factors. The possibly contrasting roles of inflammatory and homeostatic transcription factors in encoding inflammatory memory of human epithelial cells is not understood. In this proposal, I will test the hypothesis that levels of homeostatic vs. inflammatory TFs dynamically control epithelial memory formation following inflammation. My proposed studies will utilize a human keratinocyte culture system and cutting-edge expression system to modulate levels of homeostatic and inflammatory transcription factors and test their role in encoding and retaining cellular memory. Altogether, these studies will decode the mechanistic effect that transcription factors have on inflammatory memory encoding in human epithelial cells, potentially uncovering a critical disease mechanism in remitting relapsing inflammatory disorders. Understanding the cellular and molecular basis of PsO disease memory in ESPCs, as I propose here, could pave the way for developing curative therapies that limit relapse.

NIH Research Projects · FY 2025 · 2025-06

Next Generation T cell therapies for childhood cancers [NexTGen] Current treatments fail to cure many children with solid cancers. Recent advances in adult cancers such as checkpoint blockade and targeted small molecules have made little impact in childhood disease. Engineered T-cell therapies can achieve durable responses in refractory lymphoid cancers without long-term toxicity. These are precisely the characteristics required for new treatments for pediatric solid cancers. In contrast to hematologic malignancies, solid cancers are challenging due to a lack of targets, tumor heterogeneity, and hostile tumor microenvironment (TME). We posit that through advanced cellular engineering we can overcome these challenges. Our vision is that engineered T-cell therapy for childhood solid cancers will become routine within a decade. Our central hypothesis is that coupling of advanced cellular engineering along with progressive clinical development is the fastest route to developing effective T-cell therapies for pediatric solid tumors. In NexTGen, we combine detailed studies of primary tumors to discover new targets and understand how the TME subverts T- cell function. This, along with a closely coupled clinical development program will guide the progressive engineering of T-cells to result in transformative therapies. NexTGen is composed of 6 inter-connected work-packages (WPs) with work initially focused on pediatric sarcomas and brain tumors. AIMS: WP1: To identify suitable targets for engineered T-cells. WP2: To understand the TME in pediatric solid cancers. WP3: To develop receptors and other engineering components which target tumor cells and resist or modulate the TME. WP4: To evaluate the function of engineered T-cells developed in WP3. WP5: To translate approaches from WP4 and test them in clinical studies designed for maximal impact. Cancer Grand Challenges - Full Application - 2021 WP6: To promote data sharing across all WPs. METHODS: Target discovery (WP1) and TME studies (WP2) will utilize mass spectroscopy and chip cytometry respectively. Component engineering (WP3) will use protein engineering methods. To model engineered cell function, WP4 will mostly use intact tumor models such as immune PDXs. In WP5, clinical product generation will involve autologous closed system semi-automated manufacturing. WP6 uses standard and custom databases and data sharing platforms. USE OF RESULTS: Tumor target and TME data from WP1 and 2 will be uploaded to databases developed by WP6 for widespread distribution. Engineering components from WP3 and functional data from WP4 will be available for incorporation into therapeutic T-cell strategies by the entire community. Clinical study data from WP5 should lead to registration studies, improving cure rates and mitigation of long-term toxicity to realize our Vision.

NIH Research Projects · FY 2025 · 2025-06

Abstract: Historically there have been no effective treatments for geographic atrophy, the end stage of dry age-related macular degeneration (AMD). Recently, two complement inhibition treatments were shown to slow atrophic AMD progression, leading to FDA approval last year. Ideally, these and other promising treatments would be applied even earlier, before atrophy has begun. In this endeavor, early, high-risk biomarkers are needed. While the Classification of Atrophy Meetings (CAM) scheme provides staging of atrophy and nascent atrophy, it lacks granularity in the intermediate AMD stage, when these and other treatments are likely to be most effective. Macular pigments (MPs) and retinal pigment epithelium (RPE) melanosomes are beneficial for vision and protect against the development of advanced AMD. MPs are the target of Age-Related Eye Disease Study (AREDS)/AREDS2 dietary supplements, and until recently, the only accepted intervention for dry AMD. However, accurate measurement of MPs in the living eye has been challenging, and for this reason large-scale MP assessment was omitted from the landmark AREDS/AREDS2 studies. Likewise, there is no accepted method to measure RPE melanosomes/melanolipofuscin (RPEMs) in humans, so the CAM scheme assesses RPEM loss indirectly, by OCT hyper-transmission. Over the past several years, our group has pushed the axial resolution of visible light Optical Coherence Tomography (OCT) to 1 micrometer, demonstrating a multitude of bands which are not quantifiable by other techniques, including important substrates of AMD within the photoreceptors, retinal pigment epithelium (RPE), and Bruch's membrane (BM). Recently we showed quantification and localization of MPs to Henle's fiber layer for the first time in vivo, along with preliminary data showing the ability to distinguish lutein and zeaxanthin, the two major MPs. We also demonstrated direct RPEM imaging in vivo via a new spectral red-shift technique. In this proposal, the utility of the above advances for studying aging and AMD will be further bolstered with finer axial resolution and broader spectral coverage. Specifically, we will develop visible-to-near-infrared spanning OCT to image depth-resolved MPs, RPEMs and other novel outer retinal structural biomarkers for the first time, with up to 0.5 micrometer axial resolution, ~6x finer than the best commercial NIR OCT systems (Aim 1). We will investigate the spatiotemporal relationship of these biomarkers with aging (Aim 2) and early AMD (Aim 3a). Finally, we will determine whether MPs and RPEMs (or lack thereof) could serve as early biomarkers for risk of progression to atrophy, by determining association with other high-risk biomarkers (Aim 3b). If borne out by subsequent longitudinal studies, visible light OCT assessment of retinal morphology and MPs/RPEMs could identify potential beneficiaries of early dry AMD treatment.

NIH Research Projects · FY 2026 · 2025-06

PROJECT SUMMARY To generate all the cell types that comprise the human body, pluripotent cells transition through various identities before reaching their terminal cell fates by relying on a tightly regulated series of gene expression profiles regulated by transcription factors (TFs). A comprehensive understanding of the critical regulator TFs driving cellular differentiation processes will facilitate the study of human developmental disorders and the generation of clinically relevant cell types for disease modeling and regeneration. Motor neurons (MNs) from the ventral spinal cord are a clinically relevant cell type and a classic neuronal developmental model. MNs are efferent neurons that act in circuits to innervate muscles, and impairment of MNs leads to muscle atrophy and eventual loss of motor function. MNs are the primary cell type implicated in spinal muscular atrophy (SMA), a developmental disorder, and amyotrophic lateral sclerosis (ALS), a neurodegenerative disease, both of which affect nearly 1 in 10,000 people. Currently, the only available treatments for these diseases are supportive. Thus, my proposal aims to enhance our understanding of MN differentiation. The human genome codes for over 1600 TFs, but only about 50 TFs are known to be important during human spinal cord development. Recent scRNA-seq analyses reveal that more than 800 TFs are differentially transcribed during this developmental process, suggesting that the field has under-sampled the TF landscape. As an unbiased approach to identify important TFs for differentiation processes, two CRISPR screens have uncovered previously unknown TFs important for neuronal cell fates. Using a simple, TF-directed neuronal differentiation system, the first screen revealed that ZBTB18, a C2H2 zinc finger repressor that binds E-box motifs, is critical for neuronal fate downstream of NEUROG2. In humans, Zbtb18 mutations are associated with nervous system developmental defects. ZBTB18 has also been predicted to be critical for the generation of spinal cord MNs. Using a small molecule-directed MN differentiation method in mouse embryonic stem cells, the second, unpublished screen revealed 69 new TF candidates essential for progression through the stages of the MN differentiation process. This proposal aims to further characterize the TFs from these two screens by addressing the following questions: 1. What is the role of ZBTB18 in human MN differentiation? 2. Which TFs identified by the mouse screen have conserved functions in human MN differentiation? The completion of this proposal will uncover a more complete gene regulatory network controlling human MN differentiation.

NIH Research Projects · FY 2026 · 2025-06

PROJECT SUMMARY/ABSTRACT Mechanisms controlling metabolism are critical for maintaining homeostasis and are highly varied. Many metabolic control mechanisms involve metabolite sensors, which directly interact with the metabolite being sensed, eliciting a response that impacts the availability of the sensed molecule. Several metabolite sensors, such as mTORC1 and AMPK, are altered in human disease and targeted by pharmacologic agents, underscoring the importance of understanding the mechanisms by which cells and organisms sense key nutrients. Our laboratory has made fundamental contributions to our understanding of metabolite sensors that control de novo pyrimidine biosynthesis and iron metabolism, and identified mechanisms that enable biological systems to respond to changes in nutrient availability. Our proposal focuses on developing cell and mouse models in which these sensing mechanisms have been perturbed to better understand the physiologic importance of these metabolic sensing mechanisms. In the first project, we are studying the physiologic importance of an evolutionarily conserved mechanism by which cells sense pyrimidine levels via regulation of the rate limiting enzyme of this pathway, CAD. Through careful structure-function analysis, we have engineered mutants of CAD that lack this regulatory mechanism and confirmed that they exhibit increased activity with an inability to regulate biosynthetic flux. In cell-based models engineered to express CAD allosteric mutants, we will delineate the role of CAD allosteric regulation on the many connected biosynthetic pathways that support nucleotide synthesis, as well as the effects of nucleotide imbalance on the DNA mutagenesis rate. Then, we will develop animal models lacking this evolutionarily conserved sensing mechanism to delineate the impact of physiology, focusing on the function of proliferative cells, such as immune cells and barrier tissues. In the second project, we will define how dysregulation of the cellular iron-sensing rheostat impacts normal physiology. In particular, we will study how a specific component of the sensor, iron-sulfur cluster (ISC) cofactors, sense and respond to cellular iron levels by suppressing the synthesis of these cofactors in intact animals. We will study the impact of perturbed sensing on cells and tissues responsible for detecting and responding to changes in iron availability, and dissect whether these effects are mediated by two major iron response proteins, IRP1 and IRP2, using genetic knockout mice. In the third project, we will mechanistically dissect, in vitro, a novel iron sensing pathway that we identified by which ISCs control IRP2 activity. We anticipate that these iron sensing and response pathways are altered in multiple neurodegenerative diseases in which altered ISC or iron metabolism have been implicated, including Friedreich’s Ataxia.

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY As the largest payer for mental health care in the United States, Medicaid is adopting value-based payment models that link provider payments to quality in an effort to improve outcomes for high-need populations, including individuals with a serious mental illness (SMI). With over $55 billion in joint state and federal funding, Medicaid Delivery System Reform Incentive Payment (DSRIP) programs represent the most extensive effort to implement value-based payment in Medicaid to date. In DSRIP programs, which often emphasize mental health care, states contract with providers to participate in performance-based incentive payment projects, with the goal of encouraging health systems to invest in care coordination, improve surveillance of Medicaid enrollees’ care needs and outcomes, and invest in services to address enrollees’ mental health and general medical care needs. Thirteen states have implemented DSRIP programs to date. However, national evidence on the impacts of DSRIP programs on patients with SMI is lacking, both overall and for sociodemographic subgroups at high risk of experiencing poor care and outcomes. Furthermore, there is limited evidence about which features of DSRIP programs yield positive benefits—critical to understand as key program elements vary across states. The proposed study will address these evidence gaps by evaluating the impacts of DSRIP programs among community-dwelling Medicaid enrollees with a diagnosis of major depression, bipolar disorder, or schizophrenia. Using national Medicaid claims and encounter data and a difference-in-differences design, the project has three Aims: 1) to investigate the impacts of DSRIP programs on outpatient mental health and primary care use and health care quality measures indicative of care coordination and health outcomes for Medicaid enrollees with SMI; 2) examine heterogeneity in the impacts of DSRIP programs among subgroups of Medicaid enrollees with SMI along the dimensions of race/ethnicity, health complexity, disability status, and rurality; and 3) identify specific DSRIP programmatic features that are associated with positive impacts on Medicaid enrollees with SMI, leveraging variation across states in DSRIP program design. Because DSRIP programs are time-limited but intended to initiate enduring delivery system improvements, analyses will also assess longer-term impacts among Medicaid-enrolled populations with SMI. This project aligns with NIMH’s Strategic Plan to compare alternative financing models to improve care for patients with SMI and approaches to reduce documented disparities in care access, quality, and outcomes for disadvantaged subpopulations (Strategies 4.1.C and 4.3.A). Findings will provide critical evidence to guide future Medicaid payment and delivery system reforms to improve the quality and equity of health care for individuals with SMI. To maximize this project’s impact, we will work with a Policy Advisory Council comprising experts in Medicaid mental health policy from the government, research, and insurance sectors, building on our team’s track record of translating health services research to inform policy.

NIH Research Projects · FY 2025 · 2025-06

eDyNAmiC (extrachromosomal DNA in Cancer) Human genes are arranged on 23 pairs of chromosomes, but in cancer, tumour-promoting genes can free themselves from chromosomes and relocate to circular, extrachromosomal pieces of DNA (ecDNA). These ecDNA do not follow the normal “rules” of chromosomal inheritance, enabling tumours to achieve far higher levels of cancer-causing oncogenes than would otherwise be possible, and licensing cancers with a way to evolve and change their genomes to evade treatments at rates that would be unthinkable for human cells. The altered circular architecture of ecDNAs also changes the way that the cancer-causing genes are regulated and expressed, further contributing to aggressive tumour growth. These unique features make ecDNA-containing cancers especially aggressive and difficult to treat. Cancer patients whose tumours harbour ecDNA have markedly shorter survival. Despite being first seen over fifty years ago, the critical importance of ecDNA has only recently come to light, and the scale of the problem is substantial. ecDNAs are present in nearly half of all human cancer types and potentially up-to a third of all cancer patients. The collective current understanding of how ecDNA form, how they function, how they move around the cell, how they evolve to resist treatment, how they impact the immune system, and how they can be effectively targeted are lacking. We bring together an internationally recognized, pioneering interdisciplinary team of cancer biologists, geneticists, computer scientists, evolutionary biologists, mathematicians, clinicians, and patient advocates to boldly create novel insights and resources and to provide transformative solutions to one of Cancer’s Grand Challenges. A core team of experienced and productive ecDNA investigators will work with new investigators in the ecDNA and cancer fields to bring completely new perspectives and approaches to this daunting challenge. By bridging cutting-edge and diverse approaches and insights from cancer genomics, yeast genetics, epigenomics, artificial genome synthesis, longitudinal patient tracking, combinatorial and machine learning algorithms, mathematical modelling, immunobiology, and innovative chemistry we will develop a new understanding of the role of ecDNA in cancer, and we will find new ways to drug the undruggable. This bold programme, which consists of 7 work packages and a committed international infrastructure, generates new and unusual collaborations that would simply be impossible under any other type of funding mechanism. Our programme endeavours to foster bold innovative solutions to one of the hardest problems in cancer and to one of the greatest challenges facing cancer patients.

NIH Research Projects · FY 2026 · 2025-05

Project Summary A hallmark in cancer is genome-wide hypomethylation and promoter specific hypermethylation. A genome- wide reduction in DNA methylation is also observed in ageing, linking increased risk for cancer and dementia with age. This may become increasingly prevalent since the global population is aging and life expectancies are rising. Thus, managing and monitoring DNA methylations has become a priority for scientists and clinicians. Current managing strategies often target the chromatin modifiers that establish and maintain DNA methylation. Central to maintaining DNA methylation in mammals is the DNA Methyltransferase 1 (DNMT1), which is overexpression in a range of cancers such as gastric, pancreatic, colorectal, and lung cancer. However, clinical strategies to specifically inhibit DNMT1 are limited. The most common FDA-approved inhibitor lacks specificity, leading to undesirable off-target effects. It’s desirable to have specific inhibitors against DNMT1. However, developing these inhibitors may halt from missing mechanistic knowledge on DNMT1 methylation. Specifically, we are missing explanations for DNMT1’s selectivity and regulation by chromatin modification. I hypothesize the molecular interactions between DNMT1 and chromatin explains this missing mechanistic information. AIM 1 of my proposed research is to determining the cryo-EM structure of DNMT1 with specifically modified nucleosomes, revealing insights into these mechanisms. This will be followed by thorough validation through in vitro and in vivo experiments. Another strategy for managing DNA methylation is by targeting the enzymes regulating DNMT1. A significant histone posttranslational modification regulating DNMT1, mono-ubiquitinated H3 (H3Ub), currently has no identified deubiquitinating enzyme. Our research has identified a deubiquitinase that can remove H3Ub in vitro, and preliminary structural studies revealed that it exhibits a unique mechanism. AIM 2 of my proposed research involves characterizing this H3Ub deubiquitinase in cells, understanding how it regulates DNA methylation, and resolving the deubiquitination mechanism using cryo-EM. In summary, my research focuses on uncovering the mechanisms of DNA methylation and it regulation, aiming to open therapeutic avenues for age-related diseases and cancer.

NIH Research Projects · FY 2026 · 2025-05

ABSTRACT The expansion of somatically mutated clones is prevalent in hematopoiesis with profound implications for physiological aging and across a myriad of pathologies. This has been recently highlighted by the discovery of the inflammatory disorder – vacuoles E1 enzyme X-linked autoinflammatory somatic (VEXAS) syndrome. VEXAS is caused by somatic mutation in the ubiquitin-activating enzyme E1 (UBA1) gene that arises in hematopoietic stem cells (HSCs). Mutated UBA1 leads to accumulation of misfolded proteins, activation of the unfolded protein response and ultimately systemic inflammation accompanied by severe clinical manifestations. However, we currently lack the ability to target disease-initiating mutant HSCs, as the mechanisms that lead to HSC inflammation, differentiation bias and survival are unknown. This limitation stems in part from the fact that somatic clones are admixed with wild-type HSCs, limiting the ability to define mutant-specific phenotypes with either bulk or single-cell techniques. To overcome this gap, we have developed genotype-aware single-cell multi- omics techniques that are specifically designed to map somatic genotypes to phenotypes. These tools turn the limitation of admixed mutated and wild-type cells into an advantage, allowing for direct comparison in primary human samples of mutated cells to wild-type cells residing within the same bone marrow environment. Our proof- of-principle studies demonstrated that we can leverage these tools to pinpoint UBA1 mutation-specific HSC perturbation, that can be leveraged for selective targeting. Our preliminary data show that UBA1-mutant HSCs have increased upregulation of the unfolded protein response pathway through PERK activation, suggesting a compensatory mechanism for mitigating proteomic stress to promote survival in mutant cells where normal protein degradation is disrupted, which we validated in vitro. Moreover, this approach enables the characterization of how the impacts of a somatic mutation vary as a function of cell type, providing insights into mechanisms of clonal outgrowth that cannot be obtained through bulk analysis. Here, to test the hypothesis that UBA1-mutant HSCs resist proteome toxicity via dysregulated signaling pathways, we will directly analyze VEXAS primary patient samples using single-cell multi-omics to map the impact of UBA1 mutations on HSC chromatin profiles, gene expression and protein expression. Moreover, given the critical role of the bone marrow niche on HSC biology, we will apply advanced tools for spatial transcriptomic profiling to identify candidate cell-extrinsic mechanisms supporting mutant HSC survival, defining altered cell-cell interactions in VEXAS syndrome. Finally, we will use new in vitro and in vivo model systems to mechanistically interrogate and functionally validate key factors that promote disease phenotypes, representing potential targets for the development of novel precision treatments. Collectively, these efforts and new techniques will provide novel insights into VEXAS biology, and further provide a framework for deciphering the critical factors that are disrupted in disease-initiating cells and the microenvironment in somatic mosaicism and hematological disease more broadly.

NIH Research Projects · FY 2026 · 2025-05

Genome-Wide Association Studies (GWAS) have proven remarkably successful in discovering genetic variants associated with human complex traits and diseases. However, the functional mechanisms of these variants remain poorly understood. Most traits are under natural selection, and their genetic basis is shaped by pop- ulation genetic processes. Consequently, integrating molecular and cellular understanding with those from population genetics can provide valuable insights. In this project, we propose new conceptual and statistical approaches that embody this interdisciplinary perspective. To implement and test our models, we will leverage large-scale biomedical datasets, including the UK Biobank and the All of Us biobank. Aim 1: Understanding what genes contribute most to complex traits. Most GWAS variants are non-coding, and their target genes are unknown, a crucial aspect for understanding biology and applications such as drug development. To bridge this gap, one set of approaches integrates GWAS with external functional data. Another strategy uses rare disrupting mutations within coding regions of genes. However, these methods have yielded disparate results. To address this, first, we will develop population genetics models to understand the types of genes prioritized by GWAS versus rare coding variants. Second, focusing on blood cell traits, we will examine how quantitative measures of gene importance based on these two approaches compare with and complement each other. Aim 2: Characterizing gene-by-gene and gene-by-environment interactions. The significance of genetic interactions in human complex traits has been debated, partly due to technical limitations as well as a lack of conceptual un- derstanding of how interactions arise. However, characterizing these interactions is crucial for various reasons, including for personalized medicine. To address challenges associated with previous methods, we present two new approaches. First, we propose a novel model-driven approach to leverage interactions for identifying key trait-relevant genes, considering how genetic and environmental perturbations are funneled through gene reg- ulatory networks. Second, we will explore interactions at the gene level, as opposed to the commonly studied variant level interactions. Aim 3: Developing approaches to improve accuracy and interpretability of polygenic scores (PGS). Interest in using PGS, genetic predictors of disease, is growing in clinical settings. However, a major limitation of PGS is their relatively modest predictive power. We aim to enhance PGS prediction by in- corporating prior functional information, with a particular focus on gene-level annotations often overlooked in current approaches. Another limitation of PGS is that, by design, they collapse all genetic data into one score, offering no insight into the underlying biological components of the disease in any given case. To address this, we propose decomposing PGS by tissue to uncover intermediate mediating processes. In summary, the successful completion of this project will enhance our conceptual understanding of complex trait genetics and will provide valuable insights for utilizing genetic findings in disease prediction and drug development.

NIH Research Projects · FY 2026 · 2025-05

Summary This proposal leverages Big DNA technology to produce mouse models of a variety of human diseases. The underlying hypothesis tested in our earlier work and continued in this proposal is that changes in human non- coding DNA that underlie human disease susceptibility will translate into appropriate disease phenotypes in the mouse when the entire human genic region of interest is inserted into a predefined location in the mouse genome. We refer to such animals as GREAT-GEMMs (Genomically Rewritten and Tailored Genetically engineered moused models). Furthermore, GREAT-GEMMs will serve as a resource for testing therapeutic interventions against human disease. These animals will be uniquely useful for cutting edge therapies like gene therapies, CRISPR based therapies and allele specific oligonucleotide (ASO) therapies which depend on exact human DNA sequences as targets. Our work is based on our recently developed ability to synthesize and precisely edit 50-300+ kilobase DNA constructs, and then to precisely delivery them to mouse embryonic stem cells (mESCs) and subsequently produce mouse models for human disease.

NIH Research Projects · FY 2025 · 2025-05

Project Summary While considerable progress has been made investigating the neural mechanisms underlying speech articulation, less is known about how the brain plans spoken language. Efficient, rapid speech planning is critical for enabling turn-taking interactions during conversation. Planning dysfunction has been linked to several disorders, including Parkinson disease (PD). To investigate the neural foundations of this key cognitive process, the Long lab recently used electrocorticography (ECoG) to identify a compact frontal network that is selectively active during the planning of both structured and spontaneous spoken exchanges. A central component of this network is the caudal middle frontal gyrus (cMFG), which represents a novel language planning area. The study also used direct electrical stimulation to perturb cMFG which caused preparatory deficits such as response errors and reaction times. These results indicate that cMFG is a critical speech-related planning region, yet raise important clinical questions. Do neuropathologies that impact patients’ speech also affect cMFG function? And how do the interventions we use to treat these diseases affect cMFG? Thus, dissecting cMFG function at a neural circuit level will yield fundamental insights into the neural mechanisms of language generation and its relationship with different neuropathologies. In this proposal, I therefore focus on the relationships between neuropathology, speech planning, cMFG function, and neuromodulatory treatment in patients with PD by utilizing the access provided by awake insertion of deep brain stimulation (DBS) electrodes. PD is a devastating neurodegenerative disorder caused by the loss of dopaminergic neurons. In addition to motor symptoms such as bradykinesia and tremor, PD patient exhibit speech dysfunction. The mechanism speech deficits in PD are poorly understood, but preliminary work implicates impaired speech planning. Furthermore, the effect of DBS therapy, a mainstay of PD treatment that significantly improves motor symptoms, is unclear – evidence demonstrates that only a subset of patients experiences long-term improvement in speech function despite an improvement in the motor functions required for speech such as laryngeal motion, suggesting a limited ability to improve the higher-order process of speech planning. Here I will leverage the diversity of patients at our center undergoing the placement of DBS electrodes to compare cMFG function in patients with PD and other neuropathologies, such as cervical dystonia and essential tremor, that do not significantly affect speech planning, to determine the effect of PD and DBS therapy on cMFG function and clinical speech function in PD patients. I will therefore test the central hypothesis that cMFG planning activity is perturbed in PD, and a predictor of patients’ speech improvement with DBS therapy.

NIH Research Projects · FY 2026 · 2025-04

Project Summary/Abstract Minipuberty, a brief window during the first six months of life when reproductive hormones surge, may be a particularly vulnerable period for endocrine disruption by phthalates and bisphenols, endocrine-disrupting chemicals (EDCs) with both estrogenic and anti-androgenic activity that infants are highly exposed to via disposable diapers, wipes, baby lotions, shampoos, and plastic baby bottles. Exposure to EDCs during critical periods of early development can alter ovarian and testicular tissue, which may influence future reproductive development and function, including timing of pubertal maturation and subsequent fecundity. To date, only three cross-sectional studies have examined endocrine disruption during minipuberty, and while results have differed, all have found some associations between bisphenols and/or phthalates and infant reproductive hormones. None has examined associations between EDC exposure during minipuberty and anogenital distance (AGD), a measure that has been associated with maternal prenatal bisphenol and phthalate levels as well as adult reproductive health outcomes. The current project, nested within the New York University Children’s Health and Environment Study (NYU CHES), an ongoing prospective birth cohort, will include 480 full-term singleton infants whose mothers have provided repeated urine samples during pregnancy and examine both in utero and concurrent chemical exposure in relation to hormones and AGD in minipuberty. During 2 and 4-month postnatal study visits, urine and blood will be collected from the infants, and urine and breast milk will be collected from their mothers. Infant AGD will be measured by trained study staff members at birth and during both postnatal study visits. Maternal prenatal urine, child postnatal urine, and maternal breast milk will be screened for bisphenols and phthalates. Unlike prior studies that have focused only on chemicals for which analytic standards are available, we will examine both known and unknown bisphenols and phthalates using a novel approach that will leverage advanced computational methods for analyzing non-targeted high-resolution mass spectrometry (HRMS) data. Concentrations of nine reproductive hormones and two proteins will be quantified in infant serum via high performance liquid chromatography-electrospray ionization-tandem mass spectrometry. Aims include: 1) evaluating longitudinal associations of maternal prenatal urinary bisphenol and phthalate levels with infant reproductive hormone concentrations during minipuberty, 2) quantifying associations of infant urinary bisphenol and phthalate levels with infant reproductive hormone concentrations during minipuberty, and 3) examining joint effects of infant chemical and hormone levels on AGD during minipuberty. We hypothesize that phthalate and bisphenol exposure during both prenatal and postnatal periods will be associated with infant reproductive hormones, that both chemicals and hormones will be associated with AGD, and that associations will be sexually dimorphic. Regression analyses will incorporate advanced statistical methods for the reduction of high- dimensional data and for analyzing effects of chemical mixtures.

NIH Research Projects · FY 2026 · 2025-04

Project Summary/Abstract Non-cardiac surgery (NCS) is a major iatrogenic stressor that can unmask subclinical cardiovascular (CV) disease. Biomarker surveillance in the perioperative period of NCS identifies patients with unrecognized or subclinical CV disease at risk of long-term adverse CV outcomes. Myocardial injury after NCS (MINS), defined by a post-operative elevated troponin, with or without ischemic symptoms, is associated with short and long- term CV complications and mortality. Unfortunately, treatment pathways to reduce long term CV risks after non-cardiac surgery have not been defined in patients with MINS, limiting enthusiasm for biomarker screening. The long-term goal of the proposed research is to carry out an international multisite randomized clinical trial to evaluate perioperative biomarker-based precision care with targeted long-term use of a low-dose direct oral anticoagulant and high-intensity statin therapy to improve CV outcomes in patients with MINS. The successful design and execution of the future clinical trial is dependent on identifying study sites that are high volume surgical centers with sufficient frequency of post-operative troponin surveillance, refinement of study entry criteria and study interventions that will promote robust recruitment and study retention based on both clinician and participant preferences, and demonstration of study feasibility through a pilot randomized controlled trial. The current application proposes three objectives; for Objective 1, site surveys will be designed and distributed to acquire data on the number of potential participants with MINS at potential study sites, approaches to perioperative biomarker surveillance, current post-operative management of MINS, and potential barriers to enrollment. For Objective 2, questionnaires based on clinical scenarios will be designed and distributed to characterize clinician equipoise for treatment based on post-operative cardiac biomarkers overall and according to demographics, biomarker thresholds, clinical risk factors, surgical subtypes, and bleeding risks. For Objective 3, a pilot randomized trial of low-dose direct oral anticoagulant and high-intensity statin versus usual care in 50 patients with MINS will be conducted to determine enrollment feasibility and adherence to therapy at 2 months. A mixed methods approach that integrates qualitative data collected from patient interviews and quantitative methods based on Best-Worst scaling surveys and discrete choice experiments will be implemented to determine patient preferences for therapy after non-cardiac surgery (based on attributes including CV benefit, bleeding risks, convenience and costs). The data obtained for each of the objectives will be used to assess feasibility and optimize study design (entry criteria, study endpoints, sample size calculation, site selection) and recruitment strategies for the future randomized clinical trial studying biomarker-based care in post-operative patients at elevated CV risk.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY Statistical learning (SL) is a fundamental cognitive process that enables the brain to rapidly extract regularities from continuous experience. SL is a key component of many cognitive functions, for example, the ability to acquire words during language development. There has been a tremendous amount of behavioral research on SL, which is now accompanied by a growing neuroscience literature. These latter studies have revealed that both the cortex (e.g., superior temporal gyrus; inferior frontal gyrus) and the hippocampus are involved in SL. However, there exists no comprehensive account of what computations these regions perform and how these regions interact at a circuit level. Further, it remains unknown how SL emerges at increasing levels of complexity from rudimentary chunking based on transitional probabilities to the acquisition the rules of nested tree structures, such as in language. The broadest objective of our proposed work is to build and test a mechanistic neurobiological circuit theory of SL along the hierarchy of SL complexity. We hypothesize that SL occurs through dynamic interactions between the hippocampus and cortex. Testing this hypothesis requires a method that is both spatially precise and time resolved (with millisecond timing for quantifying neural dynamics). We will use non-invasive magnetoencephalography (MEG) in healthy participants alongside invasive electrophysiology in epilepsy patients, namely intracranial EEG (iEEG) with cortical surface electrodes and depth electrodes in the hippocampus. With high density hybrid depth electrodes, we will further enhance the spatial resolution in the hippocampus at the subfield level. To track the rapid evolution of statistical representations across brain regions, we will employ a novel neural frequency tagging (NFT) approach. NFT tracks SL by revealing brain rhythms at the frequency of regularities embedded in a continuous speech stream. Equipped with this cutting-edge toolkit, we will pursue our objectives across 3 aims that explore the mechanisms of SL at increasing levels of complexity. In Aim 1, we will examine functional coupling between the hippocampus and cortex during basic statistical learning of transitional probabilities using subfield resolution hippocampal recordings from iEEG and whole-brain source analysis in MEG. In Aim 2, we will examine how abstract rule-learning emerges in the brain. In Aim 3, we will investigate how SL unfolds during learning of hierarchical learning of nested structures. We hypothesize that learning specific vs. abstract regularities (i.e., rules and nested hierarchies) leads to differential engagement of the hippocampus and neocortex, respectively, resulting in reversal of information flow between hippocampus and neocortex. These findings will enhance our circuit-level understanding of SL, advancing the fields of language and learning, and highlighting potential new diagnostic and therapeutic avenues for comorbid cognitive deficits in neurological disorders.

NIH Research Projects · FY 2025 · 2025-04

PROJECT SUMMARY In contrast to breast and colon cancers, where molecular pathology tests are routinely used to improve the accuracy of disease prognostication over routine histopathology, there are no validated molecular tests for locally advanced, node-negative melanoma (Stage II). Existing molecular biomarkers, particularly commercial tests developed to manage localized melanoma, have not robustly demonstrated clinical validity or utility as evidenced by the lack of recommendation by the National Comprehensive Cancer Network Melanoma Guidelines and other organizations. Recently, pembrolizumab, an anti-PD-1 immunotherapeutic agent, was approved as adjuvant therapy for surgically resected stages IIB and IIC melanoma based on data from a randomized, placebo- controlled clinical trial. Although recurrence-free survival (RFS) at the 18-month post-surgical follow up showed a statistically significant benefit associated with pembrolizumab, the RFS in the placebo group is fairly high. Given the potential toxicity of immunotherapy, and its variable efficacy and high cost, we need more accurate tools to appropriately select patients who have a high probability of tumor recurrence, and spare surgically cured patients the risks of overtreatment. Several publications, as well as our own preliminary data have identified strong associations between aberrantly methylated DNA loci and melanoma survival outcomes. Indeed, we identified a 13-probe signature using the EPICMethylation v1.0 array that was highly accurate in identifying melanoma recurrence and mortality among patients with stage II melanoma. The goal of the current proposal is to refine and validate (analytically and clinically) the recurrence prediction signature using a large prospective cohort of stage II melanoma patients whose tumors are analyzed with the updated MethylationEPIC v2.0 array. The UH2 phase will establish the minimum amount of tumor needed to reliably detect a melanoma signature (technical sensitivity), and will establish the precision and reproducibility of the assay. We will also examine the potential interfering effect of melanocytic nevi when they are associated with melanomas, and will conduct inter- laboratory harmonization studies prior to the UH3 studies. In the UH3 phase, we will use the analytically validated assay to: 1) analyze stage II melanoma tumors from a prospective cohort of patients with a minimum of three years of follow up data (among non-relapsed patients); 2) refine the recurrence prediction model; and 3) validate the model in a separate group of patients. The final deliverable will be a recurrence-prediction model that combines clinicopathological factors with a set of differentially methylated loci to more accurately classify patients into high- or low-risk for recurrence than a model based on clinicopathological factors alone. Since the Infinium MethylationEPIC BeadChip v2.0 array is currently in use in clinical laboratories, the results of this project could be quickly tested in other patient cohorts, incorporated into clinical utility trials, and broadly disseminated to the health care community at large.

NIH Research Projects · FY 2025 · 2025-04

ABSTRACT One of the biggest challenges for the development of Coronavirus Disease 2019 (COVID-19) vaccines and therapeutics is the emergence of SARS-CoV-2 variants with immune-escape or resistance mutations. Multiple evidence points to the chronic infection of immunocompromised hosts, especially individuals with hematologic malignancies, as one of the main mechanisms for the emergence and spread of these variants. While most people with a competent immune system successfully clear SARS-CoV-2 infection within days, some patients with hematologic malignancies and weakened immunity get persistently infected for months with virus replicating often at high titers. As for other RNA viruses, SARS-CoV-2 replication can lead to the rapid accumulation of mutations over time. Thus, persistent infection of an immunocompromised host provides the timeframe during which the virus accumulates more genetic mutations than expected from individual infections without the need of transmission to another host. Moreover, these individuals could remain contagious for longer periods of time and sustain transmission to the community of variants potentially associated with virus fitness advantages, including increased transmissibility or resistance to COVID-19 vaccines or treatments. Which host immune background enables chronic infection, what specific selection acts on the virus, and what effects on the host do emerging mutations exert over the course of the disease are currently unknown. Moreover, there are no tools that allow the early identification of subjects that will develop prolonged infection. We hypothesize that specific defects in B and T cell populations that favor prolonged infection can be leveraged for the development of an early prediction tool to identify subjects with protracted infection where the virus is accumulating mutations. To address this, we will integrate patient level and epidemiological data with immune profiling and SARS-CoV-2 deep sequencing to: (1) determine the immune defects linked to prolonged replication or acute disease; (2) ascertain the effect of different immunosuppressive conditions and therapeutics on SARS-CoV-2 genetic diversity within the infected host. Our studies will advance our understanding of the immune mechanisms involved in SARS-CoV2 persistence in the immunocompromised host and inform the development of optimal therapies and public health interventions to prevent the emergence and spread of new viral variants. This approach, if successful, is also relevant to other respiratory viruses.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY Acute lymphoblastic leukemia (ALL) is the most prevalent malignancy in children. Although the five-year survival rate for ALL has approached 90% over the last 50 years, ALL’s invasion of the central nervous system (CNS), specifically the meninges (protective membrane layers that cover the brain and spinal cord), remains a significant clinical problem. Standard-of-care treatment for every child diagnosed with ALL includes chemotherapy delivered directly into the cerebrospinal fluid, and this regimen can cause multiple serious adverse events detrimental to normal neural development. Despite efforts to explain what attracts T-ALL to the CNS, it is still unclear why ALL is commonly found in the nutrient-limited meninges. Understanding how leukemia cells infiltrate the CNS is essential to furthering the development of targeted therapies for this disease. Among the different subtypes of ALL, T cell ALL (T-ALL) has the highest tendency to present with aggressive CNS disease, so we will focus our work on T-ALL. In spite of the dogma that the CNS is an immune privileged site, lymphocytes do enter the CNS in some settings, and previous studies have identified two major routes of lymphocyte trafficking into the meninges. During inflammation, effector T cells extravasate from blood across specialized venules into the cerebrospinal fluid. More recently, myeloid cells, developing B cells and B cell ALL (B-ALL) have been found migrating from the calvarial (superior portion of the skull) bone marrow into the meninges via bridging channels. Both paths are thought to require integrins. Our proposal will address major questions that arise from this prior knowledge: 1. Do T-ALL cells traffic through bridging channels in the calvaria to seed the meninges? 2. Are integrins required for T-ALL entry into the CNS? Using novel imaging techniques, we have the unique opportunity to characterize a major route of T-ALL entry into the meninges (Aim 1). We will also determine whether or not integrins are important for T-ALL CNS infiltration (Aim 2). Results from this work will provide significant insight into the development of targeted CNS-directed therapeutics for T-ALL patients.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY AND ABSTRACT Pancreatic cysts are common lesions that are frequently detected incidentally on imaging scans. Intraductal papillary mucinous neoplasms (IPMNs), the most common of these lesions, have the potential to harbor cancer or develop into cancer over time. Treatment options include either a high-risk operation or active surveillance, which risks leaving a potentially curable cancer untreated. The decision between surgery and surveillance requires knowledge about the risk of cancer in the lesion, the risk of surgery required to remove it, and a patient's individual preferences regarding various possibilities, such as leaving a potential cancer untreated or undergoing an unnecessary surgery. In practice, this treatment decision currently relies on cancer risk estimates that are flawed because of biased samples and recommendations from treatment consensus guidelines that do not incorporate patients' preferences. This K08 proposal will address the following three specific aims: Aim 1: Quantify individualized risk of cancer in IPMNs; Aim 2: Elicit patients' preferences to inform decisions about surgery versus surveillance for IPMNs; Aim 3: Develop a decision model for choosing between surgery and surveillance for IPMNs. This study is innovative in its reducing bias in estimates of cancer risk for patients with IPMN; its elicitation of patient preferences for patients with precancerous lesions; its application of a modeling approach to individualized decision making; and its development of a decision analytic model that can be tailored to patients' risk thresholds. Our findings will inform a subsequent R01 to evaluate the effects of a prescriptive decision model on treatment decisions and outcomes. The candidate is a surgical oncologist with education and experience in health policy and health services research whose long- term goal is to improve the quality of surgical decisions, particularly for treatment of the many premalignant lesions that are identified incidentally. The specific objectives of this career development award are to (1) obtain training in risk prediction methods using real world data; (2) acquire expertise in preference elicitation and shared decision making; and (3) build expertise in decision modeling. This K08 award would position the candidate to become a leader in research to improve surgical decision-making.

NIH Research Projects · FY 2026 · 2025-04

The perception of time, and more generally, the use of temporal information, is an integral part of our everyday experience. It is thus an essential capability of the brain. Despite its importance, the network underlying the ability to time events on relatively short time scales (i.e., seconds or less) is not fully known. We believe the cerebellum is a strong candidate for being a member of this network for several reasons. It has a well- established role in timing motor responses, and the near constancy of its intrinsic circuitry suggests that it should perform similar computations for both its motor and non-motor functions. Furthermore, our preliminary data from a perceptual timing task provide evidence that the lateral cerebellum plays a role in perceiving the duration of sensory events. Thus, we propose to investigate the cerebellum's role in time perception using electrophysiological and optogenetic techniques in combination with a standard (temporal bisection) and a novel (trianchor bisection) interval timing task. In these tasks, rats discriminate auditory stimuli based on their duration for a reward. In Aim I, we will selectively manipulate the activity of identified cerebellar neuronal populations using optogenetic tools in order to provide evidence of a causal link between the activity of lateral cerebellar neurons and the perceived duration of the sensory stimuli. We will test how task-related information is encoded by specific classes of cerebellar nuclear neurons, including cerebellar nuclear cells that project to the thalamus and cerebellar nuclear cells that receive input from crus 1 of the cerebellar cortex, a region implicated in cognitive functions and that is interconnected with prefrontal cortical areas. Various optogenetic stimulation patterns will be tested for their effects on timing behavior in the temporal bisection tasks to investigate which spike train parameters may be used to encode task-related information. In Aim 2, we will record from cerebellar neurons and determine the correlates of their activity with the animal's performance on the temporal bisection task. We will also investigate the possibility of other behavioral correlates of lateral cerebellar activity, and determine whether temporal and non-temporal information is encoded by the same or separate neuronal populations. The information gained through these experiments will improve our understanding of how the cerebellum encodes information about time perception and how it interacts with other brain regions involved in this process. Such knowledge should also improve our understanding of how dysfunction of the cerebellum contributes to a variety of neurological and psychiatric disorders.

NIH Research Projects · FY 2026 · 2025-04

Cognitively stimulating interactions such as reading, talking, and playing promote Early Relational Health (ERH) and support positive childhood experiences (PCEs) and have been an outcome of focus in many national cohorts and federally-funded intervention trials of children and families. There is considerable need to quantify cognitive stimulation, yet existing methodological approaches (e.g., observations, interviews) are time consuming and costly, limiting their use in studies where these methods are not feasible. The StimQ2 offers a parent-report alternative, which addresses multiple concerns presented by other measures of cognitive stimulation. It is a validated instrument designed to assess cognitive stimulation from infancy through the preschool period using an interviewer-administered questionnaire. It consists of structured questions, can be used in any setting, requires no observation, and can be administered without substantial training; it is available through free download. It was also designed to reduce social desirability bias and is one of the only measures that assesses multiple domains of cognitive stimulation. The instrument has been used extensively in research (in over 100 publications, translated to at least 10 languages). However, interview-based instruments still present challenges including staffing, time, and associated costs, resulting in a demand for measures that can be completed directly by parents through remote/online administration. We have therefore revised the StimQ2 for self-administration (StimQ2SR) and it is now being used in three large scale studies examining parenting, early childhood development, and school readiness among families across the United States, with plans to administer it in a fourth study (>2,000 participants total). The use of the StimQ2SR in these studies presents a unique opportunity to examine the psychometric properties, criterion-related validity, and alternate forms reliability of the measure in the context of existing and ongoing initiatives. In this study, we will establish the validity and reliability of a self-report measure of the StimQ2, which will enable researchers and clinicians to easily and inexpensively assess cognitive stimulation in the home through a psychometrically sound parent self-report measure. Thus, the proposed study has two goals: Aim 1: Assess psychometric properties of the StimQ2SR. Aim 2: Assess criterion-related (concurrent, predictive) validity and alternate-forms reliability of the StimQ2SR. StimQ has been used across a broad range of research that requires assessment of cognitive stimulation. Establishment of reliability and validity for the self-report version of the measure would increase practicality for broad use, with potential applicability to the vast majority of early childhood developmental research, as well as clinical and educational practice. This work is highly relevant to recent NICHD priorities related to developmental interventions and outcome measures.

NIH Research Projects · FY 2026 · 2025-04

The process by which the brain is assembled into an organized structure in which cell bodies, axon tracts, and dense synaptic neuropils occupy consistent locations is not well understood. In particular, the potential role of tangentially projecting neurons in organizing brain structure merits further investigation. Transient tangential pioneers in the subplate of the developing human cortex are thought to establish a framework for long-range connections, and defects in these neurons have been implicated in the pathogenesis of neurodevelopmental disorders. Tangentially projecting neurons can more readily be studied in the Drosophila visual system, which is amenable to rapid genetic analysis. Recent advances in understanding cell fate specification, gene expression in individual cell types, and connectivity have made this a relatively well described model system in which to address developmental and functional questions. However, visual projection neurons in the largest optic lobe, the medulla, have been excluded from many of these analyses. Recent results show that Plexin A provided by these tangentially projecting neurons organizes the layered structure of the medulla neuropil, emphasizing their importance for optic lobe assembly. This exploratory proposal will focus on characterizing the development and function of medulla visual projection (MeVP) neurons. The first aim will use lineage tracing to determine which neuroblasts give rise to MeVP neurons. As MeVP neurons constitute a small subset of all medulla neurons, these cells will be partially purified to facilitate a targeted transcriptomic analysis of their gene expression profiles. The results of this analysis will in turn enable the development of further tools that can be used to study and manipulate MeVP neurons. The second aim will investigate the mechanisms that direct MeVP neurons to send dendritic projections perpendicularly to the majority of medulla neurons and axonal projections into the central brain. Transgenic RNAi will be used to deplete guidance receptors that are expressed in these neurons and the effects on their projections will be examined. In addition, targeted ablation of MeVP neurons or their processes will reveal whether they provide cues other than Plexin A to organize the medulla neuropil. If so, these cues will be identified by RNAi knockdown of candidate transmembrane or secreted proteins derived from the transcriptomic analysis in Aim 1. Integrating this class of neurons into current models of the development of the visual circuitry will provide a more complete description of the system, and will potentially shed light on the role of tangentially projecting neurons in the developing human brain.

NIH Research Projects · FY 2024 · 2025-03

SUMMARY More than 1.1 million people in the United States (US) are living with human immunodeficiency virus (HIV) infection, and an estimated 30% of people living with HIV (PLWH) have evidence of chronic kidney disease (CKD). Compared to the general population, the rate of end-stage renal disease (ESRD) among PLWH is tenfold greater and mortality on dialysis is 19-fold higher. Contributors to CKD in PLWH include comorbidities shared with the uninfected population, HIV-specific factors, and genetic variants; however, the interplay of these various determinants remains incompletely understood. Existing CKD risk prediction tools for PLWH have low sensitivity and insufficient positive predictive value for clinical decision-making. The ability to risk- stratify PLWH and distinguish those at highest risk for future development of CKD from those at low risk is critical to optimize care and patient outcomes. PLWH at high risk can be targeted for interventions to slow CKD progression and improve survival, including earlier establishment of nephrology care and referral for transplantation; while identification of those at low risk allows for the development of a living donor selection framework specific to PLWH, effectively expanding HIV+ to HIV+ transplantation to include living donors. We hypothesize that the impact of HIV on CKD risk varies by the interplay between comorbid conditions, HIV- related factors, and genetic variants, and distinct phenotypes of PLWH with high and low CKD risk exist. To better understand this relationship, we will leverage the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS), a unique prospective clinical cohort with > 34,000 participants, and will address the following unique aims: (1) to explore the association of unique HIV-related processes and clinical characteristics with risk for CKD; (2) to explore the association of genetic variants with risk for CKD and correlate histologic findings with genetic risk; and (3) develop a tool for predicting CKD risk among PLWH. Stratification by risk for future development of CKD is critical for identifying those PLWH at highest risk that would benefit from early nephrology care and referral for transplantation and those at lowest risk that could be eligible for living kidney donation. Using an existing cohort of PLWH representative of the US HIV population, with time varying data and DNA for genotyping, to inform CKD risk prediction is necessary, practical, and novel. Our findings will contribute new insights into the relationship between HIV and risk for kidney disease.

NIH Research Projects · FY 2025 · 2025-03

SUMMARY The demand for kidney transplantation continues to greatly exceed the supply, and living kidney donors remain a critical source of organs for their loved ones. Living donor kidney transplantation (LDKT) has decreased in the US since 2004, and importantly, significant geographic disparities in likelihood of LDKT have been identified, with the southeastern US having the lowest rates. Transplant candidate-related and potential living donor-related factors, including difficulty asking family/friends to donate on one’s behalf and lack of knowledge about the donation process, respectively, have been implicated in lower donation rates. Programs have been developed to separate the advocacy role from the transplant candidate in order to overcome barriers associated with asking someone to donate on one’s behalf, and have demonstrated increases in living donor inquiries. Importantly, these programs were developed and implemented in resource-intense urban settings that afforded ready access to high-speed internet, cell phone service and close geographic proximity to urban- based transplant centers, limiting their generalizability to low-resource settings like the rural, southeastern US. Moreover, these programs failed to include targeted interventions to improve potential living donor comfort with the evaluation process, impeding sustained increases in LDKT. Living donor selection is a comprehensive process that begins with potential donor inquiry, screening of potential donors for absolute contraindications to donation (e.g. solitary kidney), evaluation, and ultimately approval. This process is time-consuming, overwhelming, and involves complex and frequent interactions with the healthcare system. Not surprisingly, many potential living donors withdraw from the process prior to approval and donation. Multiple studies have demonstrated the feasibility and efficacy of patient navigator programs in improving outcomes, including more efficient use of healthcare systems. In order to address knowledge gaps within existing programs designed to increase living donation, we utilized the RE-AIM framework to develop and implement a novel Living Donor Navigator Program (LDN). LDN combines advocacy-training to overcome barriers in initiating conversations with and identification of potential living donors with the use of non-clinical navigators to guide donors through the evaluation process. Early results indicate a 7-fold increase in likelihood of an approved donor among LDN participants compared to non-participants; however, assessment of LDN reach and adoption demonstrated that geographic disparities among participants exist. We hypothesize that expansion of the LDN program to include telehealth delivery will overcome geographic disparities in access and facilitate sustained increases in living donation. To this end, we will address the following aims: 1) Conduct qualitative assessments to identify facilitators for LDN telehealth participation, 2) Implement a LDN telehealth program, and 3) Compare the effectiveness of telehealth LDN model vs. standard of care for increasing living kidney donation.