Icahn School Of Medicine At Mount Sinai

NIH Research Projects · FY 2026 · 2026-05

Project Summary/Abstract Temporal lobe epilepsy (TLE) is a debilitating disorder that includes pervasive memory impairments that significantly impact quality of life, yet have no available treatment options. In both patients and rodent models of TLE, altered neural circuits lead to both hypersynchronous events like seizures, interictal epileptiform discharges (IEDs), and high frequency oscillations (HFOs), as well as desynchronization, with reduced coherence of oscillations and neural phase locking across regions. These changes in synchronization within and across brain regions are likely to disrupt normal cognitive function and contribute to memory impairment. One important mechanism of synchronization in the healthy brain is the dentate spike, a large-amplitude event that can occur along with synchronous neural activity across the brain. Yet, little is known about how these events are initiated, how they drive synchronous neural activity, and how they contribute to spatial memory. In Aim 1 of this proposal, we will use in vivo electrophysiology with silicon probes to characterize how neural activity is synchronized across medial entorhinal cortex (MEC) and hippocampus during type 2 dentate spikes (DS2s), which are hypothesized to be driven by inputs from layer 2 stellate cells in MEC. We will optogenetically identify these MEC2 stellate cells and both stimulate and inhibit them to determine their causal role in DS2 generation and neural synchronization. Then, in Aim 2, we will examine how DS2 rates and neural synchronization are altered in the pilocarpine-induced status epilepticus mouse model of TLE. In addition, we will record and directly manipulate MEC2 stellate cells during a cognitive task to determine their causal role in spatial cognition, and how they mediate memory impairment in epilepsy. Together, these Aims will determine the precise neural circuits that drive DS2 events and associated neural synchronization, and test how these events and synchronization processes are disrupted in chronically epileptic mice.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Cystic fibrosis (CF) is a multisystemic, autosomal recessive disorder with the majority of morbidity and mortality extending from lung disease. Given the benefits that older children and adults with CF have derived from cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies, it is anticipated that early childhood – or even in utero – treatment with CFTR modulator therapies may significantly delay or even prevent the development of CF lung disease. The role of CFTR protein in fetal lung development, and thus the potential impact of early CFTR modulator therapies, has yet to be fully elucidated. The proposed research project aims to better understand the pathogenesis of CF lung disease and the impacts of deficient CFTR protein on fetal lung development while overcoming a general roadblock in the study of many pediatric lung diseases, the scarcity of available human material. Previous immunohistochemistry studies in the fetal CF lung described a three-week delay in the developmentally regulated pattern of CFTR protein expression as well as an early, intrinsic, pro- inflammatory state. Leveraging a three-dimensional, in vitro and in vivo, lung organoid model that undergoes branching morphogenesis and alveologenesis – thus recapitulating early fetal lung development – we will characterize CFTR gene transcript expression and CFTR protein expression and function and articulate the transcriptome and proteome of normal and CF lung organoids. We hypothesize that CFTR protein deficiency in the fetal CF lung results in pro-inflammatory transcriptomic and proteomic profiles in respiratory epithelial cell populations and that this can be reasonably demonstrated using a lung organoid model. To test our hypotheses and validate the findings in the lung organoids, we will also articulate the cellular multi-omes in fetal normal and CF lungs, characterizing any disease-related cellular, transcriptomic, epigenomic, and proteomic changes. The proposed research project will provide critical insights into the pathogenesis of CF lung disease and establish a new, well characterized, in vitro and in vivo, model system of the CF lung that can be leveraged in future research endeavors (e.g. viral disease modeling, therapeutic testing). The proposed research project has the potential to identify the earliest pathogenic changes in the CF lung, determine the pulmonary impact of the application of in utero CFTR modulator therapies, and determine the need for alternative, novel treatment modalities to more readily change the early trajectory of CF lung disease.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Deficiencies in interpretation and memory of emotional social interactions are debilitating symptoms in many neuropsychiatric disorders including autism and schizophrenia and lack effective treatment. This is largely due to a poor understanding of the neural basis underlying valence-association of social memories which enables normal functioning of these processes. While neutral social memory (novel versus familiar) has been extensively explored, the circuit and synaptic underpinnings of valence-associated social memories are largely unknown. Recent findings indicate that distinct neural circuits mediate social and non-social memory. Moreover, due to the dynamic nature of social relationships, social valance representation requires more flexible updating compared to object valence and thus likely underlies distinct mechanisms. Therefore, there is an urgent need to investigate social memory valence in order to understand the pathogenesis of maladaptive social behaviors. The hippocampal subregion ventral CA1 (vCA1) has been found to regulate neutral social memory and non-social valence and indeed hippocampal abnormalities are prevalent in autism spectrum disorder (ASD). To address this knowledge gap, our overall objective is to uncover the circuits mediating positive and negative social memories and identify hippocampal cell types supporting the distinct valence representations and valence updating. Our preliminary data show several vCA1 input regions with differential activity following a positive or negative social interaction. Further, inhibition of the vCA1 impaired valence-associated social memories, which is likely dependent on differential neuromodulation. Based on those results, we hypothesize that differential inputs activate selective cell types in the vCA1 to mediate the formation and updating of specific social emotional memories. Therefore, we will pursue three Specific Aims: 1) Identify and manipulate neuromodulatory inputs into the vCA1 which selectively mediate positive social memory, 2) Uncover and manipulate neuromodulator inputs into the vCA1 which selectively control negative social memory, 3) Identify vCA1 cell type interactions involved in positive and negative social memory updating. In Aim 1 and 2 we will use optogenetics in Cre-driver lines to manipulate neuromodulatory inputs into the vCA1 as well as in vivo fiber photometry to record neuromodulator activity during positive and negative social interactions. In addition, we will use conditional knockout lines to delete neuromodulators in vCA1 input projections and assay the effect on valence-associated social memories. In Aim 3 we will combine TRAP2;Ai14 with RNAscope to identify distinct vCA1 cell types involved in positive and negative social memory representations and use slice electrophysiology to elucidate synaptic interactions between “positive” and “negative” ensembles. Since impaired social memory and emotional processing of social interactions are prevalent symptoms of ASD, research elucidating the neural basis of these social cognitive processes is essential for the much-needed therapeutic progress.

NIH Research Projects · FY 2026 · 2026-04

Summary Ebola virus (EBOV), a filovirus, causes periodic outbreaks with high fatality rates. To understand the basis for viral pathogenesis, emergence, and to devise control strategies, it is important to define the mechanisms that underlie EBOV assembly and release of infectious virus. The VP24 protein, produced by one of seven viral genes, is a 24 kDa multifunctional protein unique to the filovirus family. EBOV VP24 blocks cellular responses to interferons (IFN) by preventing nuclear translocation of tyrosine phosphorylated STAT1 (pSTAT1), a transcription factor central to antiviral IFN signaling. VP24 accomplishes this by interacting with importin α (IMPA) nuclear transport proteins, preventing binding and nuclear import of STAT1, a key transcription factor needed for IFN responses. That VP24 interacts with IMPA nuclear import factors suggests that VP24 can traffic into the nucleus. In addition, transfection studies identified a nuclear export signal (NES) at the C-terminus of EBOV VP24, further supporting nuclear its trafficking. However, whether EBOV VP24 undergoes nucleocytoplasmic trafficking and the functional significance of this trafficking remain to be determined. VP24 also plays a critical but incompletely understood role in viral genome packaging and production of infectious viral particles. Most notably, VP24, the EBOV nucleoprotein and EBOV VP35 together form filamentous nucleocapsid structures, called nucleocapsid- like structures (NCLS) that are morphologically indistinguishable from the nucleocapsids present in EBOV virions. The presence of VP24 also renders NCLS competent for actin-dependent transport. Fundamental questions remain including how VP24 facilitates actin-dependent transport and the specific molecular features required for NCLS formation and trafficking. Our Preliminary Data indicates that VP24 can traffic into and out of the nucleus and that disruption of IMPA binding significantly impairs virus growth at a late stage in the replication cycle. Disruption of nuclear export function completely abrogates infectious particle production. Consistent with these observations, an NES mutant VP24 recombinant virus could not be recovered. Providing mechanistic insight, initial studies on the NES mutant VP24 suggest that it is significantly impaired for actin-dependent trafficking. Finally, proteomic analysis suggests that VP24 recruits components of the Wave regulatory complex (WRC), a regulator of Arp2/3 dependent actin polymerization via its NES sequence. These data support roles for VP24 IMPA binding and NES sequences in virus production and suggest that the NES may recruit the WRC to promote NCLS trafficking. The proposed studies will determine how VP24 NES sequences recruits the WRC to promote actin-dependent trafficking of viral nucleocapsids and incorporation into viral particles, and it will define the IFN-dependent and IFN-independent consequences of VP24-IMPA interaction.

NIH Research Projects · FY 2026 · 2026-04

Project Summary: Parietal epithelial cells (PECs) line Bowman’s capsule and neighbor podocytes on the opposite side of Bowman’s space without any physical barriers separating the two cell populations. In proliferative glomerulopathies such as rapidly progressive glomerulonephritis (RPGN), the most aggressive form of acquired glomerular disease, podocyte injury leads to the pathogenic activation and unchecked proliferation of PECs. This causes an agglomeration of activated PECs within Bowman’s space causing crescent formation, which contributes directly to disease progression and severity. Although severe podocyte injury is the initiating insult in all forms of proliferative glomerulopathy, how injured podocytes communicate with PECs to induce their activation is not well understood. To investigate whether this podocyte-to-PEC crosstalk is mediated by podocyte-derived exosomes, we induced nephrotoxic serum nephritis (NTSN), a widely used mouse model of RPGN, in podocyte-specific exosome reporter mice. In this model, podocyte-derived exosomes carry a GFP- tag which allows them to be tracked and to identify uptake by recipient cells. In this way, we identify activated PECs as the major kidney recipient cell type for podocyte-derived exosomes in NTSN. Pharmacological inhibition of exosomes in NTSN mice reduced PEC activation, crescent formation, and proteinuria. Furthermore, treatment of cultured PECs with urinary exosomes derived from NTSN mice caused increased proliferation and expression of PEC activation markers, whereas urinary exosomes from control mice had the opposite effects. Taken together, these findings suggest that podocyte-derived exosomes contribute to PEC activation. To identify responsible podocyte-derived exosomal cargo miRNAs, we performed small-RNA sequencing of podocyte-derived exosomes isolated from the urine of NTSN and control mice. Quantitative PCR of glomeruli and urinary exosomal pellets validated that upregulated miRNAs were increased in the NTSN model. One of the most upregulated miRNA cargoes was miR-155, an oncogenic miRNA, whose role in proliferative GN is unknown. Gain-of-function studies in cultured PECs shows that miR-155 is sufficient to drive PEC activation. We hypothesize that a direct podocyte-to-PEC signal mediated by uptake of podocyte- derived exosomes by PECs drives PEC activation in proliferative glomerulopathy and that exosomal cargo miR-155 is a key driver of the PEC activated phenotype. We propose three specific aims: 1) We will validate that uptake of podocyte-derived exosomes by PECs is central to PEC activation in NTSN. 2) We will determine the role of podocyte-derived exosomal miR-155 cargo in mediating PEC activation in NTSN. 3) We will characterize the role of podocyte-derived exosomal cargo miRNAs in human proliferative glomerulopathy. Overall, the goal of this proposal is to establish podocyte-to PEC signaling by exosomes as a major cause of PEC activation and in this way, to identify potentially druggable targets to treat or prevent proliferative glomerulopathy.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY The maintenance and function of a tissue/organ depends on cell-cell interactions among different cell types. The cell-cell interactome responds and regulates the tissue microenvironment (ME) which is altered in physiological processes such as development and aging, or during the onset and progression of various human diseases. Spatial transcriptomics offers an opportunity to systematically characterize the structural organization of the ME and its changes in various diseases. On the other hand, it requires the development of sophisticated computational methods to achieve these goals. In this project, we will develop a unifying modeling framework, called, ONTraC, and apply it to systematically characterize ME organization in multiple mammalian tissues. A unique feature of the ONTraC framework is that it uses the niche as the basic structural component instead of a cell, as commonly done. The specific aims are: 1. To develop a new framework for constructing niche trajectories from spatial transcriptomic and epigenomic data; 2. To extend the ONTraC framework for analyzing subcellular RNA localization patterns; and 3. To comprehensively characterize the ME organization in acute kidney injury mice through a systems biology approach. Taken together, our proposed research will generate powerful computational tools that will enable biologists and clinicians to investigate the structure and function of ME organization in health and diseases.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY / ABSTRACT The mammalian hematopoietic system develops in the early embryo through a series of spatio-temporally separated programs, each of which harbors different functional potential, culminating in the specification of the hematopoietic stem cell (HSC). The overall goal of our research is to understand the origins and development of each program in the embryonic hematopoietic system. Where does each developmental program originate from? How does it develop? Why is each different? And, is there clinical utility to embryonic cell types that are no longer found in adult donors? Dr. Sturgeon's prior work has focused on these questions, through the lens of human pluripotent stem cell (hPSC) directed differentiation, leading to the pivotal discovery of hematopoietic commitment occurring very early, within nacent mesoderm, referred to as hemogenic mesoderm (HM). The proposed research program builds upon Dr. Sturgeon's productive research track record to delineate the molecular and transcriptional mechanisms by which HM gives rise to the embryonic hematopoietic programs. Dr. Sturgeon has shown that HMs are found in multiple immunophenotypically distinct subsets, each of which are specified in ACTIVIN/NODAL- and/or WNT-dependent processes. Further, Dr. Sturgeon has found that each HM first gives rise to a hemogenic endothelial cell (HEC) population, in VEGF- and RA-dependent processes. HM express genes associated with early gastrulation, yet each HM is highly restricted, ultimately each giving rise to a specific hematopoietic program, such as yolk sac-like erythromyeloid progenitors (EMPs), or intra- embryonic-like definitive multipotent progenitors (MPPs). Finally, Dr. Sturgeon has found that hematopoietic lineages common across multiple HM populations harbor distinct functional properties from one another. Building off these groundbreaking findings, the research program is divided into 3 projects. The first project will delineate the signal, transcriptional, and epigenetic mechanisms underlying how each hematopoietic program is specified and functionally restricted. These studies will improve our ability to obtain progenitors from each program, including the HSC. The second project will define the mechanisms regulating how HECs give rise to different lineages. Finally, the third project will continue our studies on the translational potential of hematopoietic lineages from each developmental program. Collectively, these studies will provide us with a more comprehensive understanding of hematopoietic development. This is of fundamental importance to basic biology, and the insights generated from these studies will have clinical implications, such as the in vitro generation of HSCs or other embryonic hematopoietic lineages for a wide array of regenerative medicine applications.

NIH Research Projects · FY 2026 · 2026-04

SUMMARY Nipah virus (NiV) is a highly lethal zoonotic paramyxovirus from the Henipavirus genus that causes severe respiratory disease and encephalitis in humans. To date, no antivirals have been approved for treatment or prevention of these infections. We will develop and test peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO)-based compounds as anti-NiV therapeutics. Phosphorodiamidate morpholino oligomers (PMO) are water soluble, nucleic-acid-like antisense agents having nuclease resistance. They form stable duplexes with complementary RNA, affecting function. PMOs are FDA-approved to treat forms of Duchenne muscular dystrophy. PMOs can be conjugated to a cell-penetrating peptide to produce peptide-PMO (PPMO) which enter cells without the need for transfection. Aqueous solutions of PPMOs have shown considerable antiviral efficacy against a number of RNA viruses. We evaluated the anti-henipavirus potential of PPMOs using the non-pathogenic henipavirus Cedar virus (CedV) at BSL2. We designed PPMOs to target the start codons for the mRNAs encoding the three viral proteins essential for viral RNA synthesis- nucleoprotein (N), phosphoprotein (P) and large protein (L). These exhibited low micromolar activity versus CedV replication in Vero cells. A pilot test of PPMO targeting NiV N and P demonstrated anti-NiV activity in cell culture. That the P gene is a viable target is notable because the NiV P gene also encodes two critical virulence factors, V and W, which disable the type I interferon response. Because V and W share the same N-terminus as the P protein, an inhibitor of P translation will also block V and W expression. Therefore, a single P-targeting PPMO could disable viral RNA synthesis and simultaneously promote antiviral IFN-I responses, potentially enhancing antiviral activity. Building on these data, we will design PPMOs to target NiV N, P and L mRNAs. These will be tested for inhibition against live NiV at BSL4 and mechanism of action assessed by using a BSL2 NiV minigenome assay. We will test the hypotheses that antiviral activity of PPMOs correlates with suppression of translation of the targeted mRNA and determine whether targeting the P start codon will augment PPMO antiviral effects by suppressing expression of V and W. We will then test the best performing PPMO in vivo, using a hamster model. We will use airway administration because (1) Respiratory symptoms are a significant component of NiV infection. (2) In hamsters, infection can spread from the airway to the central nervous system (CNS) via the olfactory bulb. (3) Prior studies have used respiratory delivery and respiratory NiV challenge to test therapeutic candidates. (4) We recently demonstrated that PPMOs delivered directly to the airway at a 1 mg/kg dose reduced SARS-CoV-2 lung titers by >104 infectious units per gram lung tissue, and our Preliminary Data demonstrates that intranasal delivery to mice results in sustained PPMO effects throughout the upper airway and extending into the olfactory bulb. The in vivo studies will include assessment of tolerability, tissue distribution and efficacy against NiV of the top performing PPMO. We expect these efforts to yield a candidate PPMO for further development.

NIH Research Projects · FY 2026 · 2026-04

Project Summary This proposed MAGen development site aims to develop genomics and multi-modal artificial intelligence (AI) models to transform personalized cancer risk assessment, monitoring, and prevention. A substantial gap exists between the theoretical potential of genomics-based AI predictions and their practical application in clinical and population healthcare settings. The clinical classification of genetic variants is hindered by insufficient data to classify ultra-rare variants, particularly those found in non-European populations. Moreover, despite significant advances in AI across fields, we lack AI models that can combine diverse streams of health data to accurately predict disease risk across a person’s life course. Finally, the real-world effectiveness of these AI models remains untested and their ethical, legal, and social implications (ELSI) are unclear. To address these challenges, our primary goal is to develop state-of-the-art (SOTA) AI models that can accurately identify pathogenic variants affecting DNA repair genes and predict cancer risks over the life course of high-risk carriers, thereby optimizing screening and prevention strategies in an ELSI-informed manner. Our multidisciplinary team comprises experts in computational genomics, AI/ML, health informatics, statistical genetics, medical genetics, population health, oncology, and ELSI research from Icahn School of Medicine at Mount Sinai (ISMMS), Boston Children’s Hospital/Harvard, and Columbia University, and has complementary and extensive experience in consortium and team science projects. In our proposed project for MAGen, Aim 1 will develop robust genomic AI models for identifying protein-disrupting missense variants that confer high cancer risks. Aim 2 will combine other genetic factors, including common and rare variant polygenic risk scores (PRS), and non-genetic factors, including EHR, longitudinal lab markers, SDoH, and digital pathology, to predict cancer risk over the life course and optimize screening recommendations for carriers. Aim 3 will cross-validate AI models in real-world population biobanks and determine their clinical impact. Aim 4 will construct an ELSI framework and conduct ELSI projects to evaluate the multi-faceted impacts of AI-driven genetic diagnostics. Aim 5 will disseminate AI model/predictions, cross-validation data, and ELSI recommendations. The completion of these Aims will bring genomics-based and multi-modal AI closer to the advancement of personalized medicine in real-world settings by more accurately classifying pathogenic variants, optimizing the timing of screening, and identifying key lifestyle and medical prevention strategies that could ultimately save lives from cancer.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract Our daily lives require constant decision-making in which we pursue potential rewards at the expense of potential costs. The integration of costs and benefits is an essential component of decision-making. Abnormal decision- making, including increased pursuit of high cost/ high reward options, is a transdiagnostic symptom of multiple psychiatric and neurological disorders including depression, post-traumatic stress disorder, addiction and many others. Stress exposure can induce these disorders and lead to long-term alterations in decision-making. Here, we will explore interactions between neural circuits and endocrine mechanisms that contribute to the pursuit of high cost/high reward options in mouse models of chronic stress exposure. Our previous work showed that the striosomal patches of the dorsomedial striatum are essential for integration of cost and benefit and that dysregulated activity in striosomal inputs contributes to persistent pursuit of high cost-high reward options in previously stressed rodents. Our previous work also showed that ghrelin receptor activity contributes to processing of reward and cost, and that the ghrelin receptor is present within the striatum. Here, we hypothesize that striosomal projection neuron hyperactivity is a key factor in stress-induced cost insensitivity, and activation of ghrelin receptor in the striosomes plays a causal role in this shift in decision- making. Using a naturalistic cost-benefit decision-making task that does not require food deprivation as motivation, we will examine decisions to pursue high costs paired with rewards and lower costs paired with rewards. We will record from striosomal projection neurons within and following different types of chronic stressor exposures to identify the “tipping point” at which abnormal striosomal activity and altered decision-making first emerge. We will use optogenetics to manipulate activity patterns in stress-exposed mice to “correct” stress- induced changes in decision-making and to “mimic” stress-induced striosomal firing patterns in unstressed mice to induce cost insensitivity. We will pharmacologically activate ghrelin receptors and determine whether this is sufficient to induce cost insensitivity and striosomal hyperactivity in unstressed mice. We will perform virus- mediated knockdown of the ghrelin receptor in striosomes and determine whether this is sufficient to prevent stress-induced changes in decision-making in stress-exposed mice. The goal of our proposed work is to identify a mechanistic basis for the shift in circuit activity and decision-making after repeated exposure to stressors, thereby advancing towards our long-term goals of predicting individuals who are at-risk for altered decision- making, and providing new peripheral and central targets for intervention to restore normal decision-making in the face of trauma and psychiatric illness.

NIH Research Projects · FY 2026 · 2026-03

Project Summary Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) worldwide, yet current therapies fail to adequately address critical drivers to its progression: lipid- driven inflammation, immune dysregulation, and fibrosis that drive its progression. Triggering receptor expressed on myeloid cells 2 (TREM2), a receptor specifically expressed on macrophages, has emerged as a pivotal regulator of lipid metabolism and immune responses in metabolic disorders, but its role in DKD remains poorly understood, necessitating further investigation. Our preliminary data suggest that TREM2 exerts a protective role in DKD by mitigating lipid-driven injury and inflammation. Furthermore, we identified the TREM2 R47H mutation, a known risk factor for impaired macrophage function in neurodegenerative diseases-as a susceptibility variant for CKD. Soluble TREM2 (sTREM2), a cleavage product of TREM2, correlates with kidney function decline and inflammatory biomarkers in DKD patients, underscoring its potential as both a prognostic indicator and a therapeutic biomarker. Together, these findings establish TREM2 as a compelling target for elucidating DKD pathogenesis and for the development of innovative biomarkers and therapies. To address these knowledge gaps, we propose three synergistic aims. Aim 1 will dissect the functional and disease-modifying consequences of the TREM2 R47H mutation on macrophage function and DKD progression, leveraging genetic models and lipid-stressed macrophage assays. Next, we will define the molecular mechanisms underlying sTREM2 cleavage, its functional role in macrophage-tubule crosstalk, and its utility as a biomarker for disease progression and therapeutic response (Aim 2). Finally, we will explore the therapeutic potential of TREM2 activation, employing a novel agonist antibody to restore macrophage functionality, reduce lipid-driven injury, and improve kidney outcomes in DKD models (Aim 3). By integrating genetic, mechanistic, and therapeutic strategies, this research aims to unravel the intricate interplay between macrophage lipid metabolism and immune regulation in DKD. Moreover, it seeks to establish a robust framework for TREM2-targeted therapies and sTREM2-based biomarkers, advancing precision medicine approaches to transform the care and prognosis of patients with DKD.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Despite significant advancements in genomic medicine, its integration into Internal Medicine (IM) remains limited. This program will seek to address barriers at the residency training level. Mount Sinai has been at the forefront of addressing this need for genomic medicine training during Internal Medicine training. Mount Sinai has stood up initiatives such as a specialized Genomic Medicine track within the IM residency and the development of the Genomic Education in Medicine (GEM) platform, which provides web-based resources to support genomic education for IM residents. This one-day conference will bring together leaders from IM residency programs across the United States, as well as genomic medicine experts and clinicians to assess current efforts and share innovations for integrating genomics into training. The event will focus on identifying barriers to adoption, such as limited expertise and competing priorities, and developing strategies to overcome these challenges across diverse residency environments. Through a collaborative one-day process, attendees will create a “consensus agenda for education in and implementation of genomic medicine” within IM residencies, which will then be refined and finalized through follow-up virtual meetings. The goal is to publish a proposed education agenda and implementation strategy to support those IM training programs that seek to bring genomic medicine implementation into their curriculums.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Building on our track record in genomic research, clinical trials, and genomic medicine in patients from NYC, we propose to develop new frameworks to bring genomic risk into clinical care to promote preventive health. Polygenic risk scores (PRS) are entering an exciting phase where they are poised to improve health outcomes for myriad complex diseases through enhanced risk stratification and clinical decision making. However, major challenges exist for clinical PRS implementation today, including issues of access to leading-edge genomic technology, research, and testing, and barriers to uptake of medical recommendations. To address this, Mount Sinai experts in statistical genetics and population genetics, with decade-long experience in building methods for genetic risk prediction, will work together to rigorously develop robust clinical PRS tests. We will integrate clinical PRS with standard clinical risk and family history information to generate genomic risk assessments for up to 15 common diseases. Drawing on Mount Sinai’s century of experience delivering excellent patient care, we will recruit 2,500 adult and pediatric patients into a clinical trial. We will estimate participants’ individualized risk for each condition, and investigate the impact of genomic risk communication to patients and their physicians, including patient understanding and uptake of recommended risk-reducing interventions. We will explore attitudes, barriers, and communication preferences related to genomic risk assessment. Knowledge gained will be used to guide the development of a new patient-facing digital platform supporting patient education and communication of genomic risk. We will track patient engagement with their results through the platform, and assess the impact of individualized genomic risk assessments on patient-reported psychosocial outcomes and experiences. As of today, the path to effectively integrate genomic risk into clinical care in busy health systems, is unclear. Hence, we are partnering with clinicians, scientists, industry experts, and community stakeholders to explore a range of strategies to assess, communicate, and reduce disease risk, in order to maximize the efficiency of genomic medicine delivery.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Temporal lobe epilepsy (TLE) is a complex neurological disorder that is characterized by spontaneous, reoccurring seizures and often presents with debilitating cognitive comorbidities including learning and memory deficits. Current treatments for TLE are ineffective at managing cognitive comorbidities and often exacerbate these symptoms. The mechanisms underlying cognitive impairments in TLE are poorly understood, but learning and memory deficits are thought to arise when TLE pathologies disrupt the normal function of hippocampal circuits that support these cognitive processes. Circuits in the hippocampal dentate gyrus (DG) are known to support learning and memory and have been shown to be disrupted in TLE patients and in animal models of TLE. Recently, Dr. Shuman showed that the spike timing of DG interneurons is disrupted in TLE. Additionally, he showed that restoring proper spike timing of DG interneurons with closed-loop optogenetic stimulation decreased seizure susceptibility in TLE mice. Because proper spike timing in the hippocampus is an important mechanism that supports learning and memory computations, I hypothesize that DG interneuron spike timing is also important for behavior. In aim 1, I will test this hypothesis by using closed- loop optogenetic stimulation to alter the spike timing of DG interneurons relative to ongoing theta oscillations. I predict that disrupting DG interneuron spike timing in non-epileptic mice will impair learning and memory while restoring the disrupted spike timing of DG interneurons in TLE mice will restore learning and memory deficits. While optogenetic approaches are great for assessing the causal relationships between physiological processes and behavior, there are a number of barriers that limit the translational potential of optogenetics. In aim 2, I will employ a novel circuit-editing tool to increase connectivity between DG interneurons and their upstream inputs in the medial entorhinal cortex (MEC) with the goal of increasing feedforward inhibition in the DG. I hypothesize that increasing connectivity to DG interneurons will decrease seizure susceptibility. Additionally, I predict that this approach will restore the proper spike timing of DG interneurons because inputs fire at the same preferred phase of theta as DG interneurons and are not disrupted in TLE. Circuit-editing is a novel technique that has never been applied to epilepsy. Successful implementation of this approach could result in a transformative gene therapy for epilepsy patients and will inform how feedforward inhibition in the DG normally supports hippocampal physiology. The following research project and training plan were designed to help me grow both scientifically and professionally, and support from this grant will be invaluable as I continue to work towards my goal of becoming an independent researcher. The outstanding opportunities provided by the Shuman lab and Mount Sinai provide the ideal training environment for me as I pursue my postdoctoral fellowship and ultimately a career in academic research.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT Persons with serious illness suffer from poor symptom control, decreased quality of life (QoL) and poor communication with their healthcare providers, especially in terms of goals of care discussions (GOCD). Palliative care, when offered alongside disease management, offers improved symptom control, QoL, communication, caregiver satisfaction and reduced caregiver anxiety. Due to a limited specialty-trained palliative care workforce, however, patients and their caregivers often cannot access these benefits, especially in the community. These needs are particularly acute in advanced cancer and HF, the two leading causes of death in the US which also model the most common illness trajectories. The dynamic nature of these illnesses presents distinct symptom patterns and changing functional state that require an adaptive, dynamic model of palliative care delivery. Yet, workforce shortages prevent scaling of existing community-based specialty palliative care models. To meet patient/caregiver dyads' needs with a limited workforce, new models that deploy palliative care clinicians based on patient's illness trajectory and changing needs are required. The innovative TIER-PALLIATIVE CARE (TIER-PC) model provides the right level of care to the right patients at the right time. TIER-PC increases the number and intensity of specialty trained palliative care disciplines added to the dyad's care team as their symptoms worsen and function declines. In Tier 1, patients who can care for themselves and have easily managed symptoms, receive support from a community health worker (CHW) trained to elicit illness understanding in a culturally competent way. In Tier 2, for patients with poorer function and mild symptoms, a social worker (SW), trained in serious illness communication, joins the CHW to further elicit patients' illness understanding and goals, and provide caregiver support. In Tier 3, as function decreases and symptoms increase, an advance practice nurse (APN) joins the CHW+SW to manage complex symptoms. In Tier 4, for those patients with the poorest function and worst symptoms, an MD joins to address the most complex needs (e.g., end-of-life treatment preferences and multifaceted symptom control). The CHW follows dyads longitudinally across all tiers and re-allocates them to the appropriate tier based on their evolving needs. We will evaluate TIER-PC's efficacy in a multi-site, single blinded, two arm, randomized controlled trial. Patients with advanced cancer or HF will receive regular assessments by the TIER-PC team to: address symptom and psychosocial needs; improve illness/prognostic understanding; prescribe medications; and address goals of care. We will enroll and randomize 400 patients with HF or cancer and their family caregivers to receive TIER- PC or an augmented control. We will follow dyads for 12 months to determine if TIER-PC: improves patients' symptom control and QoL (primary outcomes), patient-reported GOCDs and caregiver satisfaction; reduces caregiver anxiety and post-traumatic stress; and decreases patients' healthcare utilization and cost. By matching demand to the scarce workforce, our scalable model can improve care for patients with cancer or HF.

NIH Research Projects · FY 2026 · 2026-03

The R00 Pathway to Independence Award will establish the applicant's independent research program as a tenure track faculty member in the Departments of Psychiatry and Obstetrics, Gynecology and Reproductive Science (OBGYN) at the Icahn School of Medicine at Mount Sinai (ISMMS). The Developmental Origins of Health and Disease (DOHaD) framework is supported by a robust literature that provides evidence for the role of environmental exposures in shaping brain and behavior development through prenatal programming. Maternal childhood maltreatment has been associated with both maternal prenatal mental health and infant emotion regulation outcomes; however, most known transmission pathways are behavioral, with limited evidence for biological transmission. Well-established behavioral pathways are through maternal mental health and parenting sensitivity influencing infant emotion regulation and mother-infant interactions. Emerging evidence supports maternal childhood maltreatment effects on infant outcomes through biological pathways such as in utero programming of brain development. Despite the

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Myelodysplastic syndrome (MDS) is a clonal hematologic malignancy characterized by ineffective erythropoiesis, cytopenias (typically anemia), transfusional iron overload, and impaired survival. Despite evidence that iron overload correlates with increased morbidity and mortality in MDS patients and that excess iron impairs erythropoiesis in vitro, whether iron chelation is warranted in the patient population remains controversial. Specifically, unlike correlatory studies showing improved hemoglobin or decreased transfusion burden with iron chelation, no such benefit was found in deferasirox-treated MDS patients in a randomized controlled trial. How iron overload impacts erythropoiesis in MDS patients is incompletely understood and few therapeutic options are available to target ineffective erythropoiesis in MDS. Furthermore, a recent renaissance in iron metabolism research has enabled us to ask the overarching question: does excess iron lead to impaired erythropoiesis in MDS and if so, by what mechanism? To address this question, we generated preliminary data demonstrating that MDS patient erythroblasts exhibit aberrant cellular iron sensing and trafficking and that iron chelation restores iron trafficking regulation to increase hemoglobin and reverse ineffective erythropoiesis paradoxically by increasing transferrin (TF) saturation in MDS mice. Iron is found in the circulation as monoferric N-, monoferric C-, or holo-TF with monoferric TF in highest concentration physiologically. We have previously shown that only monoferric-C TF impedes erythropoietin (EPO) responsiveness in mice and that only monoferric-N TF reverses ineffective erythropoiesis in β-thalassemiic mice. We therefore hypothesize that monoferric TFs are a novel translational regulatory node in MDS erythropoiesis and aim to examine in detail the underlying mechanisms thereof in Specific Aim 1. Furthermore, our preliminary data demonstrate that expression of TFR2, a known erythroid iron sensor, is increased in MDS patient bone marrow samples and erythroblasts in MDS mice; that TFR2 loss in other models ameliorates ineffective erythropoiesis; and that the effect of is dependent on signaling via TFR2. We thus hypothesize that TF iron:TFR2 mediated signaling in erythroblasts critically contributes to EPO responsiveness in MDS and aim to evaluate underlying mechanisms in Specific Aim 2. Lastly, our preliminary data demonstrate that expression of intracellular iron trafficking genes is increased in bone marrow samples from MDS patients and erythroblasts from MDS mice and that DFP normalizes the expression of iron trafficking genes and decreases reactive oxygen species (ROS) without impacting apoptosis in MDS mouse erythroblasts. We thus hypothesize that a newly described form of iron-mediated cell death, ferroptosis, in MDS erythroblasts contributes to ineffective erythropoiesis therein and aim to evaluate underlying mechanisms in Specific Aim 3. Taken together, our extensive compelling translational preliminary data supports our proposal to target how dysregulated iron metabolism contributes to the mechanisms underlying disease pathophysiology in MDS, the understanding of which will impact a clinically relevant unmet need.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT: This K23 career development award will enable the candidate, Jennifer Love, MD, MSCR, to become an independent clinician-scientist focused on improving emergency care for patients with opioid use disorder (OUD) who are exposed to xylazine and novel adulterants. Xylazine, an alpha-2 agonist and veterinary medication, has been increasingly detected with fentanyl. In 2023, xylazine- adulterated fentanyl and its health effects were declared a national toxicologic emergency. Due to its rapid emergence, limited knowledge exists regarding xylazine’s health effects. Some studies have reported prolonged sedation and necrotizing skin wounds among patients. In her pilot work, Dr. Love examined clinical effects of xylazine exposure in emergency department (ED) opioid overdose patients and found lower incidence of cardiac arrest and coma among patients exposed to xylazine. In her later work, she found that xylazine exposure was more often associated with bradycardia in the ED. In this K23, Dr. Love will develop and refine a clinical registry for ED opioid overdose patients exposed to xylazine and novel adulterants. The registry will integrate health record, toxicologic, serum biomarker and clinical outcomes data. Using qualitative interviews with people who use drugs and addiction medicine specialists, Dr. Love will refine the registry’s data elements and outcomes to reflect meaningful, targeted data collection. Dr. Love’s specific aims include (1) creating a clinical registry for xylazine-associated overdose and comprehensive ED care; (2) measuring xylazine and its metabolites in serum/blood and urine using laboratory and point-of-care assays; and (3) refining registry data elements and outcomes using perspectives of individuals with knowledge of xylazine and adulterants. To achieve her aims, Dr. Love will engage in focused curriculum and didactic coursework in data management, forensic toxicology, and qualitative research and analysis. Dr. Love will build upon her experience as an emergency medicine physician and toxicologist to gain new skills in qualitative research using semi-structured interviews, forensic laboratory analysis, clinical data management, and database quality assurance. Dr. Love has assembled an expert mentorship team of nationally funded researchers and clinicians in emergency medicine, medical toxicology, and addiction medicine. The proposed research and career development plan will allow Dr. Love to develop expertise in (1) clinical database management, (2) forensic toxicology and (3) qualitative research. The K23 will enable her transition to an independent clinical investigator focused on understanding acute and longitudinal outcomes for OUD patients exposed to xylazine and adulterants in evolving drug markets. Project completion will produce a clinical registry for opioid overdose patients who are exposed to xylazine and other adulterants, and form the basis for Dr. Love’s subsequent R01 proposal. Her future R01 will expand the registry to hospital sites across the US. The registry will critically advance ED-based toxicologic and addiction care for patients exposed to xylazine-adulterated fentanyl.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY The rising prevalence of Alzheimer's disease and related dementias (ADRD) necessitates the early identification of subgroups at high risk of developing these diseases. Recent evidence suggests that individuals with neurodevelopmental disorders, particularly autism spectrum disorder (ASD), may face an increased risk of early ADRD. However, systematic knowledge on the aging process in individuals with ASD remains limited. Our preliminary data shows a higher risk of early ADRD in individuals aged 30-70 with ASD. In Sweden we observed 6-fold higher risk for early ADRD in individuals with ASD compared to non-ASD individuals. We observed 8-fold and 3-fold higher risk for ADRD in samples from Israel and US, respectively. Furthermore, individuals with ASD exhibited a 2-fold higher risk for cardiometabolic disorders and a 10-fold higher risk for depression, both of which are significant risk factors for ADRD. Our preliminary data also shows higher risk for ADRD in relatives of individuals with ASD (1.4-fold and 1.2-fold higher in parents and aunts/uncles, respectively), suggesting potential genetic links. Given the impending aging of a large ASD population and the associated societal costs, a rigorous study is urgently needed to establish the association of ASD with early ADRD, to identify the most important contributing factors, and explore underlying mechanisms. To address these questions, our team draws on multiple unique resources with which we have extensive experience: We will use the Swedish national health registries that include diagnostic, medical, and demographic information for >5 million individuals 30-70 years old. Replication will be done in samples from the US (>100 million) and Israel (>1.6 million) for validation and generalizability of results. To strengthen inference on the relationship of ASD with ADRD, we will test clustering of ADRD in relatives of ASD patients in Sweden. Then we will test potential genetic mechanisms underlying the association of ASD with ADRD using existing genomic and sequencing data (>400,000), including from Sweden and the US. In Aim 1a we will rigorously evaluate ADRD risk in ASD using Swedish national registers. We will assess potential modifiers including sex and comorbid conditions (intellectual disability, ADHD, epilepsy). Aim 1b will further use longitudinal statistical approaches to model the impact of changing medical conditions over time, including depression and cardiovascular disease, on the risk pathway linking ASD to ADRD. Aim 2 will test for replication in datasets from Israel and the US. Aim 3a will investigate familial clustering of ADRD in ASD and Aim 3b will determine whether there are genetic etiologies shared between ASD and ADRD. By triangulating multiple large data sources, the proposed study will rigorously address significant knowledge gaps on the association between ASD and ADRD. The knowledge obtained through this study will be vital in the development of evidence-based patient care programs and early diagnostic strategies aimed at minimizing or preventing early ADRD in individuals with ASD as they get older.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY This application is submitted in response to RFA-DA-26-001: SCORCH Data Mining and Functional Validation. Human immunodeficiency virus (HIV) infects non-neuronal cells in the brain, particularly microglia, which serve as reservoirs of latent infection. HIV has deleterious effects on both non-neuronal and neuronal cell function in brain regions involved in reward, emotion, and cognition. Many of these same regions, including the nucleus accumbens (NAc), also regulate the motivational properties of opioids and other drugs of abuse. Opioid use disorder (OUD) is more prevalent in people living with HIV than in the general population, and HIV and OUD reciprocally interact, with each exacerbating the severity of the other. EcoHIV is a modified HIV strain capable of infecting microglia, macrophages, and CD4+ T cells in mice, and recapitulating key pathobiological features of chronic HIV infection in humans. As part of the SCORCH consortium, we have generated single-nucleus RNA sequencing (snRNA-seq), two-dimensional (2D) single-cell spatial transcriptomic (Spatial-seq), and 3D single- cell Spatial-seq data from the NAc of control and EcoHIV-infected mice that remained drug-naïve or had a history of intravenous (IV) opioid (oxycodone) self-administration. Sequencing data were also collected from the same groups of mice that received antiretroviral therapy (ART). Here, we will mine this unique dataset to investigate the cellular and molecular mechanisms of HIV and opioid interactions in the NAc. In AIM 1, we will analyze our sequencing data to define the genetic phenotypes and spatial organizations of the medium spiny neurons (MSNs) in the NAc that undergo the most robust transcriptional remodeling in response to HIV infection alone and in combination with opioid self-administration. This analysis will enable us to distinguish between D1- and D2-expressing MSNs, identify novel subtypes, and determine their distributions within the NAc according to established (e.g., core versus shell) or novel spatial architectures. We will also integrate our mouse sequencing data with similar datasets collected from HIV-infected and drug-experienced rats, non-human primates (NHPs), and humans, available through the SCORCH-Neuroscience Multi-omics (SCORCH-NeMO) Archive. By constructing a cross-species cell atlas of the NAc, we can prioritize HIV and opioid-responsive MSN subtypes for further analyses. In AIM 2, we will employ cutting-edge circuit mapping, electrophysiological, and molecular approaches to characterize functional adaptations in the genetically defined and spatially organized MSN subtypes that exhibit the most robust transcriptional responses to HIV infection and opioid exposure. In AIM 3, we will use the CRISPR-Cas9 system to target high-priority genes dysregulated by HIV and opioids in genetically defined and spatially organized MSN subtypes in the NAc. The effects of CRISPR-mediated gene cleavage in MSNs on IV opioid self-administration and other NAc-mediated behaviors relevant to HIV/opioid interactions will be evaluated in EcoHIV-infected mice. This highly innovative research program promises to fundamentally advance our understanding of the pathobiological interactions between HIV and opioids.

NIH Research Projects · FY 2026 · 2026-02

SUMMARY Chronic kidney disease (CKD) is significantly more prevalent among persons with HIV (PWH). HIV infection increases the likelihood of progression from CKD to end-stage kidney disease (ESKD), and HIV-associated nephropathy (HIVAN) continues to be a major cause of ESKD in PWH. Despite the widespread implementation of antiretroviral therapy, PWH remain at significantly higher risk of ESKD compared to the general population. While carriage of the apolipoprotein-L1 (APOL1) haplotype has emerged as the strongest genetic contributor to the elevated ESKD risk in PWH, this alone does not fully explain the risk, warranting further investigation into ESKD pathogenesis. In the largest genome-wide association study of ESKD in HIV to date, we identified a new locus in the EYA1 gene with the top signal conferring nearly a 5-fold increased risk of developing ESKD independent of clinical comorbidities and APOL1 haplotype. While this association was validated in two independent HIV cohorts, inconsistent results were observed in two non-HIV populations. EYA1 is a tyrosine phosphatase and transcriptional co-factor that plays a key role in kidney development and is a critical regulator of nephron progenitor cell differentiation, as evidenced by Eya1-deficient mice lacking kidneys. Our team demonstrated that Eya1 gene expression is increased in the adult podocytes of HIV-1 transgenic mice (Tg26), an experimental model for HIVAN, compared to wild type. Moreover, higher EYA1 protein expression was detected in human kidney biopsy samples from patients with HIVAN than in nephrectomy controls. Yet, how EYA1 functionally contributes to the pathogenesis of HIVAN remains unknown. Therefore, our objective is to characterize the regulatory landscape of the EYA1 locus in PWH with ESKD and conduct mechanistic studies to determine whether EYA1 directly causes glomerular damage or facilitates damage caused by HIV. We hypothesize that a) EYA1 risk locus regulates the expression of EYA1 and/or other target genes responsible for renal injury; and b) HIV infection serves as a "second hit" in EYA1 risk variant carriers, leading to podocyte dysfunction and HIVAN. In this proposal, we plan to 1) Investigate the genetic origins and fine map the novel EYA1 risk locus to identify causal drivers. We will also compare EYA1 contribution to ESKD risk in PWH versus general population; 2) Characterize kidney histology, podocyte function, and EYA1 expression in archived formalin fixed paraffin imbedded human kidney biopsies from EYA1 carriers vs non-carriers with or without HIVAN, and 3) Characterize novel mouse models of HIVAN with podocyte-inducible Eya1 expression and determine whether Eya1 induction in podocytes affects kidney disease in the presence of HIV versus no HIV. This proposal leverages strong preliminary data, transdisciplinary expertise, and access to large well-characterized cohorts to explore EYA1 as a potential risk factor and therapeutic target for HIVAN and beyond.

NIH Research Projects · FY 2026 · 2026-02

Neurogenomic studies by the SCORCH (Single Cell Opioid Response in the Context of HIV) consortium strongly suggest that brains of individuals living with HIV in the context of opioid or (polys)substance use disorder (OUD/SUD) comorbidity harbor a molecular environment permissive for HIV viral replication and risk for cytotoxic damage. This conclusion also applied to donors who showed systemic, antiretroviral drug- mediated suppression of the virus. There was a stepwise progression of transcriptomic dysregulation in OUD+HIV+ brain, culminating in widespread neuronal pathology and pronounced inflammatory signatures in microglia from individuals with poor viral suppression. The goals of the current project are two-fold. First, we aim for single molecule validation of SCORCH single cell results, by analyzing~12-20kb single molecule fiber- seq libraries from cingulate cortex of SCORCH brains carefully annotated for OUD/SUD and systemic (HIV) suppression status. We will embark on single fiber-level multiomic profiling with differential analyses to uncover effects of HIV infection on nucleosome phasing, positioning and offset at transcription start sites, together with endogenous m5CpG methylation and transcription factor footprints. Integrating single cell (RNA+ATAC-seq) data already generated from the same set of SCORCH brain cohort, with our new single molecule multiomic fiber-seq mappings is expected to provide unprecedented neurogenomic insights into the HIV and substance-exposed brain. Second, we aim for additional functional validation of SCORCH data, by employing HIV-induced lineage tracing (HILT) in human induced pluripotent stem cell (hiPSC)-derived Neuron-Astrocyte-Microglia (hiPSC N-A-Mg) tricultures, in conjunction with CRISPRi for multiplexed microglial promoter repression focused on genes that are both (i) dysregulated in SCORCH SUD+ postmortem brain and (ii) implicated in HIV expression or replication. We will assess viral integration frequency, numbers and proportions of infected microglia, and compare transcriptomes and chromatin of infected/integrated HIV+ microglia with those from exposed bystander cells. This project is a first step to validate SCORCH genomic discoveries on the single molecule level, followed by the design of novel therapeutic tools targeting opioid/substance-dysregulated genes that could foster HIV infection and spread in the brain.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY The long-term objective of this K99/R00 proposal is to provide Dr. Amelia Hicks with the expertise and skills to become an independent investigator studying the intersection of traumatic brain injury (TBI) and Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD). Her career goals are to advance the clinicopathological understanding of post-traumatic neurodegeneration (PTND), explore how diverse biological and environmental factors influence risk and resilience for PTND, and develop personalized interventions that improve long-term outcomes for TBI survivors. The proposed work is strongly aligned with the National Plan to Address Alzheimer’s disease (NAPA), which has identified research at the intersection of TBI and AD/ADRD as a key priority and highlighted the importance of cross-training in these fields to break down research siloes that impede scientific progress. In the K99 phase, Dr. Hicks will complete targeted training activities to address key gaps required to achieve her career goals. Her training objectives are to: (1) become a leader in TBI and PTND proteomics, (2) improve understanding of high level biostatistical analysis, (3) acquire knowledge of TBI and PTND neuropathology and post-mortem tissue analysis, and (4) develop strong professional skills to support transition to independence. This career development will take place within the exceptional research environment of the Brain Injury Research Center at the Icahn School of Medicine at Mount Sinai. The short-term research objective of this K99/R00 is to identify and validate the pathological and multi-domain clinical signatures of PTND. To achieve this, Dr. Hicks will use blood-based proteomic data from the Atherosclerosis Risk in Community Study (ARIC) to identify PTND-associated proteins (K99; Aim 1). Then, using multi-domain (cognitive, neurobehavioral, motor) clinical data she will identify PTND clinical phenotypes and compare clinical trajectories in PTND and ADRD (K99; Aim 2). For the independent R00 phase she will leverage the Late Effects of TBI Study (LETBI) to examine the ARIC PTND-associated proteins in blood and post-mortem brain tissue. She will also identify combinations of multi-domain clinical outcome and compare to ARIC PTND clinical phenotypes (R00; Aim 3). These findings will provide invaluable preliminary data for future research efforts including a novel and competitive R01 submission. The knowledge gained from this project will produce clinically meaningful outcomes of highest importance to patients and families by 1) characterizing clinical signatures of PTND to facilitate clinical diagnosis and prognosis, and 2) advancing pathological disease definition required to identify novel treatments for PTND. Together, the K99/R00 training and research activities will establish Dr. Hicks as one of the only investigators with cross-disciplinary knowledge of neuropsychology, proteomics, and neuropathology, complemented by advanced biostatistics training and professional skills ready to lead impactful, clinically meaningful PTND research as an independent faculty member.

NIH Research Projects · FY 2026 · 2026-02

SUMMARY Current treatments for the suppression of allograft rejection have remained largely unchanged over the last several decades, relying on systemic calcineurin inhibition, anti-metabolites, and steroids. Although effective in curtailing alloimmune responses, these systemic therapies produce significant undesired off-target effects, which often lead to early organ loss and patient mortality. There is an urgent need for innovative strategies to mitigate these critical side effects, extend transplant survival, and improve organ recipient lifespans. Among nanotherapies, antibody-drug conjugates (ADCs), represent a cutting-edge technology that combines biologics with small molecules to target specific cells. ADCs have been successful in cancer, where they leverage antibody specificity to deliver cytotoxic drugs directly to target cells, achieving impressive tumor efficacy with reduced systemic toxicity compared to chemotherapy. However, their application to the field of organ transplantation has been hindered by the high immunogenicity of the Fc portion, poor tissue penetration, and the absence of tools to track cargo delivery to the target cells, essential for controlling immunosuppression. We hypothesize that Fab-fragment drug conjugates (FDCs), which lack the limitations of ADCs, can be utilized to selectively deliver immunosuppressive drugs both intracellularly to T cells (intra-FDCs) and locally to sites of allograft inflammation (local-FDCs), while maintaining low drug systemic levels of free drug. Our approach, supported by our preliminary results, introduces an innovative design for these nanotherapies, which enables precise monitoring of drug release both in vitro and in vitro, combining both therapeutic and diagnostic (theranostic) purposes. In Aim 1 we will design and optimize an FDCs-based platform for the targeted delivery of the calcineurin inhibitor Tacrolimus, and the anti-metabolite mycophenolic acid (MPA) directly into T cells (Intra-FDCs). In Aim 2 we will establish an FDCs-based strategy to locally release the corticoid methylprednisolone at inflamed allograft sites (local-FDCs). While both intra-FDCs and local-FDCs utilize Fab fragments, they rely on independent mechanisms of action and drug-release triggers. This independence ensures that each approach can be pursued separately. This R21 application will generate intra-FDCs and local-FDCs leveraging a fluorescent theranostic platform to enable real-time tracking of their delivery and activity. This approach, while technically challenging (high-risk), offers a potentially transformative solution to a critical unmet need in transplant immunosuppression and other contexts, such as autoimmune disease (high-reward). Successful outcomes will set a clear path forward for developing these FDC strategies for human use and will constitute the basis for applications to other funding mechanisms. 1

NIH Research Projects · FY 2026 · 2026-02

ABSTRACT The proposed project addresses critical gaps in understanding the pathogenesis of progressive supranuclear palsy (PSP), a rare tauopathy characterized by debilitating motor and cognitive impairments. PSP is distinguished by its unique neuropathological features, particularly the widespread involvement of glial cells— astrocytes and oligodendrocytes—alongside neuronal tau pathology. Despite recent advancements, the specific role of glial tau biology in PSP remains poorly understood, and this research aims to uncover the molecular mechanisms driving glial tauopathy in PSP. The study integrates cutting-edge techniques, including genome- wide association studies (GWAS), spatial transcriptomics, and multiplex immunohistochemistry, to explore the genetic, transcriptomic, and cellular factors underlying PSP. Aim 1 will identify novel genetic risk loci by expanding the cohort to include diverse populations, addressing the underrepresentation of non-European ancestries in PSP genetic studies. This expanded cohort will enable the discovery of genetic drivers that have been overlooked in previous studies, facilitating a deeper understanding of the disease's genetic architecture. Aim 2 will utilize spatial transcriptomics to generate high-resolution gene expression maps of tau-positive and tau-negative glial populations in key brain regions such as the primary motor cortex and putamen. These spatial maps will be integrated with hyperphosphorylated tau immunohistochemistry to identify molecular changes linked to tau pathology in both glial and neuronal populations. By exploring these relationships, this aim will uncover the role of glial dysfunction in PSP. Aim 3 will focus on region-specific protein markers of degeneration using immunohistochemistry, examining the expression of key neurodegenerative markers and genetic candidates. This will be done through both case-control and case-only studies to correlate proteinopathies with clinical phenotypes, tau-related pathologies, and genetic findings, providing insights into PSP heterogeneity. Furthermore, this aim will deploy A.I. based algorithms of pathology quantification on whole slide images, an approach that could be leveraged in studies of other primary and secondary tauopathies. The combination of these advanced methodologies will offer new insights into the molecular pathways that drive disease progression, particularly the role of glial cells in tauopathy. Furthermore, the focus on diverse populations will ensure that the findings are globally relevant, advancing diagnostic and therapeutic strategies for PSP and related tauopathies.