Icahn School Of Medicine At Mount Sinai

NIH Research Projects · FY 2025 · 2023-09

SUMMARY Cocaine use is endemic nationwide. According to a national survey, over 2.5% of the population of individuals 12 years and older reported crack or cocaine use in the past year, accounting for over 10,000 deaths related to cocaine overdose. Recent data suggests that the COVID-19 pandemic has exacerbated substance use in the United States. Only a small minority of cocaine users seek formal treatment for their addiction, and even in those who do, the relapse rate remains disturbingly high with some studies reporting rates as high as 90%, 12 months after treatment. Relapse in addicted individuals is presumed to precipitate from the re-exposure to cues that were previously associated with drug use. Over the course of chronic drug use, these cues are afforded enhanced attention (or attention-bias), which has shown to promote motivated arousal, culminating in compulsive drug-seeking or relapse. We have used the late positive potential (LPP), an EEG-derived marker of motivated arousal to show that, unlike commonly believed, arousal to drug cues (or cue-reactivity) increases (or incubates) during the first six months of abstinence. Such incubation of cue-reactivity is posited to confer disproportionately high relapse vulnerability in addicted individuals. Our recently acquired follow-up data show that addicted individuals are able to down-regulate drug cue-reactivity (as evident via a decrease in LPP amplitude) via cognitive reappraisal (an emotion-regulation technique) training, which then leads to a reduction in spontaneous attention-bias to drug cues (quantified using eye-tracking). Here, we propose to integrate the two pieces of evidence to test whether cognitive reappraisal training can reduce the incubation of drug cue-reactivity (Aim 1) and improve clinical outcomes (e.g., reduce craving and prolong cocaine abstinence duration; Aim 2) during the first 6 months of abstinence in individuals with cocaine use disorder (iCUD). We will further explore whether changes in attention-bias to drug cues and/or blunting of incubation of cue-reactivity tracks treatment response and predicts clinical outcomes at 6 months follow-up (exploratory aim). For this purpose, we propose to enroll 126 iCUD, half of whom will be randomized to undergo cognitive reappraisal training and the other half will instead complete a control task. In this longitudinal study, participants will complete these procedures at 1-week, 1-, 3-, and 5-months post abstinence initiation, and will then come back one month after (at 6 months post abstinence initiation) for the assessment of clinical outcomes. Thus, this novel study aims to bridge between the lab and the clinic by advancing basic mechanistic understanding of a novel evidence-based intervention to provide cognitive markers for tracking treatment response and predicting outcomes in addiction. Successful completion of this study would lay the foundation for further basic and clinical studies that will examine other putative mechanisms and potentially also use the same framework for the neurocognitive examination of similar cognitive interventions in other substance use disorders as well as in other behavioral addictions.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY The Mount Sinai Center for Post-COVID care has provided specialized evaluation and treatment services for adult Long COVID patients since 2020. The Center operates as a specialty referral service staffed by clinicians, social workers and care navigators. Yet unlike other specialties, it is fully integrated in primary care (PC), which facilitates referrals, access to PC-based services like depression treatment, and seamless transitions back to PC after the need for specialty Long COVID care is complete. The program has served over 6000 patients to date. However, the Center's reach has been limited. Its two locations, in Manhattan's Lower East Side and Upper West Side are out of reach for most residents of New York City communities hard hit by COVID-19, including the minoritized and low income residents of Harlem and the South Bronx. Resource constraints, including staffing and protected time, have limited the ability of Center leaders to extend access to care for patients, reduce waiting times for evaluations, introduce practice innovations and keep up with changes in the field. For these reasons, we propose a project that would add a third site to the Center for Post- COVID care integrated in Mount Sinai's Internal Medicine Associates (IMA) PC practice in East Harlem and build resources and processes that continually improve Long COVID care and extend its reach in a sustainable way. The new practice will be staffed by PC providers with expertise in Long COVID care, a neuropsychologist, social worker and health navigators. In project Phase 1, the project team will create and regularly update clinical decision pathways to guide clinicians through the evaluation and care of Long COVID patients and embed them in the electronic medical record (EMR). We will provide patients with comprehensive, highly patient-centered and coordinated care that involves point-of-care evaluations like cognitive assessment and pulmonary function testing, care navigation, and facilitated access to PC-based clinical services like mental health care and to specialists throughout the Mount Sinai Health System. We will partner with two community- based health and social service providers to develop and implement patient engagement and referral strategies to increase awareness of Long COVID and access to care for it among Harlem and South Bronx residents, and link patients to social services for wrap-around care. We will also develop a comprehensive education program for the benefit of the specialized Long COVID team and the local PC providers, and collect and analyze data for program evaluation and continuous quality improvement. In project Phase 2, we will develop the Long COVID knowledge and clinical skills of PC physicians in IMA and other PC practices (`satellite practices), train them to use the EMR-embedded CDS and provide them access to Long COVID specialist e-consults and referrals so that they can manage Long COVID patients of low complexity.

NIH Research Projects · FY 2026 · 2023-09

In the midst of the opioid epidemic, methamphetamine use is emerging as a major substance use crisis, characterized by high relapse rates and the absence of FDA‑approved treatments for individuals with methamphetamine use disorder (MUD). One of the primary contributors to relapse is enhanced motivated arousal, or cue‑reactivity, to drug‑associated stimuli, which persists even after extended abstinence and leads to increased craving and drug‑seeking behavior. Although cue‑reactivity has been widely studied in other substance use disorders, it is insufficiently characterized in MUD, creating a critical gap in the identification of objective markers for assessing disease severity and treatment outcomes. In this bi‑phased study, we aim to identify a psychophysiological marker of methamphetamine cue‑reactivity and its incubation with abstinence, and to evaluate differences across clinically relevant subgroups. In the second phase, we will longitudinally assess the progression of cue‑reactivity, its modulation using cognitive reappraisal (CR), and the clinical impact of CR among individuals with MUD. Based on preliminary findings, we hypothesize that the late positive potential (LPP), an EEG‑derived index of drug cue‑reactivity, will track the incubation of methamphetamine cue‑reactivity and its CR‑mediated reduction, which in turn will be associated with improved clinical outcomes. In the R61 phase, we will cross‑sectionally compare LPP‑assessed cue‑reactivity between individuals actively using methamphetamine and those in early (1 – 3 months) abstinence, and examine within‑task changes in cue‑reactivity during CR. In the R33 phase, individuals will be assigned to CR training or control conditions, and cue‑reactivity will be assessed longitudinally at <2 weeks, 2 months, to 3 months following abstinence initiation. Successful completion of these aims will identify an objective, clinically informative marker of methamphetamine cue‑reactivity in MUD and clarify how its modulation relates to treatment response. This work will lay the foundation for the development of mechanism‑based interventions for methamphetamine use disorder.

NIH Research Projects · FY 2025 · 2023-09

Abstract HIV eradication requires the elimination of latent reservoirs composed by cells harboring persistent proviruses. The brain is an anatomical site that is poorly accessible to the immune system as well as therapeutic agents. It also harbors a specific type of cells, microglia, where HIV can silently persist for long periods of time. Human endogenous retroviruses (HERVs) are a group of transposable elements, which are mostly held in an inactive state by different epigenetic mechanisms. Narcotic use induces changes the epigenetic landscape that can influence latency establishment and HERV expression. This project’s goal is to test the hypothesis that the distinct HERV expression signatures detected in HIV LTR-silent infection affect latency establishment and that this can be influenced by narcotic treatment. Furthermore, latent HIV-specific HERV expression can be exploited for the discovery of HIV latency specific markers. In order to investigate these hypotheses, it is crucial to determine the precise identity of the HERV elements expressed during latency. The experimental strategy is based on our newly developed reporter virus, which distinguishes latently infected from productively infected microglia cells in combination with our established proteogenomic approach which integrates HERV-specific RNA expression analysis with mass spec analysis. Such highly specialized processing is required because of the repetitive nature of HERVs that so far has undermined their detailed investigation. The RNA and protein expression blueprint obtained will inform on the ranking of the latent HIV- specific HERVs whose relevance will be investigated utilizing state of the art CRISPR-based expression induction in primary microglia as well as for the detection their expression in brain tissue form HIV patients with and without documented history on narcotic use. We expect that the innovative experimental approach proposed will provide insight into HERV RNA/protein expression landscapes in latently infected primary microglia and offer potential causal links between latency establishment, HERV expression and substance abuse. Even though there are high-risk aspects in this proposal, the experimental strategy proposed will deliver predictable, high gain benefits in our understanding of the complex biology underlying HIV latency in the brain compartment.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY – SEX DIFFERENCES IN NEURAL CIRCUIT MECHANISMS OF AGGRESSION Aggression is a necessary, adaptive component of social behavior; however, it can become escalated and may threaten lives, increase the risk of developing psychiatric disease in victims, and incur tremendous economic burdens on society. Even though aggression can have such dramatic effects on the health and well-being of our society, we have very few treatments, owing to our still limited understanding of the neural circuit mechanisms driving aggression. In this application we first take an unbiased computational approach to identify novel circuit mechanisms of aggression. Using an iDISCO+ tissue clearing method, we broadly assessed cFos expression— an immediate early gene (IEG) induced by neural activity—across the entire brain to identify brain regions differentially activated following aggressive versus non-aggressive social interaction. We assessed cFos in ~500 brain regions—registered to the Allen brain atlas—simultaneously and examined interactions across brain regions by generating co-expression networks with weighted correlation network analysis (WCNA), a widely used data mining method for studying biological networks based on pairwise correlations between variables. In this case we examined correlations between cFos expression in brain regions and ranked the correlations based on the strength of the correlation and the number of total connections. One of the most strongly interconnected networks was within the amygdala, which is made up of a highly heterogenous cluster of brain regions and cell types that perform a diverse range of functions from controlling anxiety and fear to social behavior and reward. Using advanced Ca2+ imaging and chemogenetics, we found that activation of Esr1 glutamatergic neurons in the COAp of males during aggression was necessary for aggressive behavior. Chemogenetic inhibition of these cells increased pro-social investigation during the resident intruder (RI) test, however, it did not occlude pro- social reward/reinforcement behavior. For example, we found that previously aggressive mice will actively lever press for an intruder mouse; not to attack to the intruder, but to engage in pro-social interactions with them. Conversely, in females we find that activation of COAp neurons is necessary for pro-social encounters during the RI test. Thus, our data suggests that the COAp may serve as an important switch in both sexes—though in sexually dimorphic ways—to control the motivation to engage in pro- versus aggressive-social behavior. Based on our strong pilot data, we have designed a series of studies to better understand this phenomenon and fully characterize the role of COAp circuitry in mediating aggression and pro-social behavior. We will use chemogenetics/optogenetics, electrophysiology and in vivo Ca2+ imaging to dissect the role of COAp and downstream circuits in mediating aggression and pro-social behavior in both male and female mice. We believe that these studies will provide an important understanding of the neural circuit mechanisms governing social behavior.

NIH Research Projects · FY 2025 · 2023-09

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death and a leading cause of liver-related death. People are more likely to develop HCC if they have a chronic liver disease and chronic liver injury. Germline variants modulate the extent of scarring that occurs in response to chronic injury. Germline variants also influence the probability that HCC will arise. Germline variants interact with other factors (age, viral infections, toxic exposures, adiposity) to determine the risk that HCC will develop and to establish the characteristics of the tumor cells and their surrounding microenvironment. Specifically, the combination of genetic variants and other factors influence the types of somatic, cancer-associated DNA mutations and transcriptional changes that occur in HCC tumors. These tumors are highly heterogeneous in natural history and in their responses to cancer therapies. Because of this heterogeneity, it is critical to collect detailed information on all major HCC subclasses and to clarify the relationships among germline variants, disease presentation, and somatic cancer-related mutations. These factors influence therapeutic responses. Although five-year survival among patients with HCC is currently only about 20%, targeted therapies, including immune checkpoint inhibitors, are rapidly improving outcomes. Effective use of these therapies and the development of the next generation of precision medicines will require additional detailed information about HCC subclasses. To provide this information, this project is an innovative collaboration between experts in the Liver Cirrhosis Network and liver cancer researchers. It will yield information about the mutational signatures of HCCs in patients treated in the United States and investigate germline variants associated with advanced liver scarring (cirrhosis) and HCC. The results are expected to show that some types of cancer mutational profiles occur more frequently in individuals that have a low germline risk for cirrhosis. This information will help to identify patients who may benefit from initiating HCC screening at an earlier stage of liver cirrhosis than other patients. Aim I: We will perform whole exome sequencing on paired HCC/non-HCC specimens from HCC patients and use our in-house pipeline to identify somatic single nucleotide variants (SNVs), to find known and novel mutational signatures, to define the tumor mutational burden, and to identify mutated genes. Aim II: We will perform global transcriptomic analysis on paired HCC/non-HCC specimens to identify oncogenic drivers and computationally immunophenotype the microenvironment. Multiplexed immunohistochemistry will be used to map the molecular findings onto the histological architecture of liver specimens. Aim III: We will compare the prevalence of cancer predisposition variants in people who do and who do not develop HCC, develop a polygenic risk score for cirrhosis, and explore genetic risks for cirrhosis in the Liver Cirrhosis Network.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Non-coding RNAs (ncRNAs) constitute the majority of RNAs present within the human cell, and are potent regulators of cellular processes, including translation, splicing, and post-transcriptional messenger RNA (mRNA) control. Like humans, viruses produce ncRNAs, whose functions are still largely unknown. Given that viruses evolved to maximize the information contained within their small genomes, all viral ncRNAs are postulated to be functional. Our lab studies the mechanisms by which small viral ncRNAs modulate host and viral processes, the knowledge of which will contribute to the development of new approaches to treat human disease. In the next five years, we will elucidate the roles of two distinct viral ncRNAs classes: small nuclear RNAs (snRNAs) expressed by an oncogenic g-herpesvirus (Project 1), and a microRNA (miRNA) produced by SARS-CoV-2, a virus that causes acute respiratory disease (Project 2). g-herpesviruses are DNA viruses, which during latency induce host cell transformation and oncogenesis. The latent viral genes produce several proteins and multiple ncRNAs. During its latency, herpesvirus saimiri, a classic g-herpesvirus, expresses seven snRNAs, known as HSURs. Unlike human snRNAs, HSURs were not linked to mRNA splicing, but instead to regulating host RNA levels in the cytoplasm. Interestingly, our results indicate that HSURs predominantly localize to the nucleus, where their roles remain unknown. Additionally, we observe that HSURs selectively translocate host cytoplasmic RNA-binding proteins into the nucleus. In Project 1, we will investigate the nuclear roles of viral snRNAs to explore unknown functions for host RNA-binding proteins and to gain insights into g-herpesviral transformation. SARS-CoV-2, a large RNA virus, is the causative agent of the coronavirus disease 2019 and the source of the current pandemic. We and others have recently discovered a miRNA expressed by SARS-CoV-2, named CoV-miR-O7a, which downregulates host genes involved inter alia in interferon signaling. Our preliminary data show that CoV-miR-O7a is abundantly present inside SARS-CoV-2 virions. We hypothesize that CoV-miR-O7a (and perhaps other ncRNAs) are selectively incorporated into virions to allow for early manipulation of host gene expression. In Project 2, we will investigate the mechanism and significance of viral miRNA incorporation into nascent virions to understand as yet unknown aspects of SARS-CoV-2 pathogenesis and to describe the previously unexplored way in which viruses inhibit host antiviral responses. Our multidisciplinary approaches, combined with the flexibility of MIRA funding, will lead to the establishment of a unique research program centered around understanding of small RNA biology in the context of viral infection. In elucidating functions of small viral ncRNAs, this study will advance the fields of RNA biology and virology. Such knowledge can lead to identification of novel targets for treatment of viral disease, including virally-induced cancers.

NIH Research Projects · FY 2025 · 2023-09

Advances in biobanking and the routine collection of personal data have created new opportunities to explore potential genomic associations with complex human traits. While such research offers potential benefits, it also raises ethical concerns, including the risk of misuse, restricted access to care, and implications for the use of reproductive technologies. This project aims to guide the field in order to maximize the benefits and minimize the harms of this type of research. There is an urgent need to inform how genomic data are collected, analyzed, and reported, especially in ways that are inclusive, ethical, and socially responsible. To maximize benefits and ensure that health disparity populations are included in research that can affect them, we emphasize that research should be conducted in partnership with impacted communities. Guided by a broadly representative Executive Stakeholder Board and workgroups—including community members, advocates, clinicians, and experts in ethics, law, genomics, and health—we will explore perspectives on the risks and benefits of studying complex human traits through a genomic lens. Our work will include: Identifying gaps in the literature and defining key ethical, legal, and social issues for inclusion in future guidelines; Conducting a mixed-methods study consisting of in-depth interviews, quantitative surveys, and listening sessions with key stakeholders (e.g., researchers, clinicians, ethical and legal scholars, IRB members); Convening a national Summit to develop guidelines and recommendations through a structured and inclusive engagement process. This project will contribute to all four NHGRI/ELSI priority research areas and result in the development of best practices and standards for conducting ethically sound genomic research. The Board, Workgroups, and Summit participants will form a national network to provide ongoing leadership and guidance in this evolving field.

NIH Research Projects · FY 2025 · 2023-09

Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer death in the United States. While prevention efforts are paramount, most patients succumb to advanced HCC disease. Thus, enrollment of at-risk patients (e.g., cirrhosis of any etiology) in early detection programs is recommended in clinical practice guidelines. Longstanding challenges to improving early-stage HCC detection are suboptimal performance of the recommended surveillance tools [i.e., abdominal ultrasound and serum alpha-fetoprotein (AFP)] and the low implementation rate of surveillance programs (as low as 25% in the United States). Various studies have tried to utilize tumor nucleic acids released to the bloodstream (i.e., “liquid biopsy”) as novel early HCC detection tools, but its role in this clinical setting is largely unexplored. Up to 18% of patients with cirrhosis have indeterminate nodules detected during surveillance. In these patients, imaging is inconclusive, and patients require either a biopsy of the suspicious nodule and/or close imaging follow-up. Our project is designed to overcome these problems by using new blood-based liquid biopsy biomarkers and magnetic resonance imaging (MRI)-based radiomics. We have assembled a multi-institutional Translational Research Center including leading academic centers in NYC (Mount Sinai, Columbia, Cornell, and Montefiore). We plan to collect blood, clinical and imaging data from a cohort of 2,560 patients (early HCC cases and controls at high risk). In Aim 1, we will determine the clinical role of new liquid biopsy technologies (i.e., cell-free DNA fragment analysis and a 3-small RNA signatures from extracellular vesicles in plasma) as a novel surveillance approach in HCC. In Aim 2, we will integrate MRI-based radiomics models with our liquid biopsy technologies to better characterize indeterminate nodules in cirrhosis. Our project is timely and uniquely poised to respond to the imperative of developing noninvasive biomarkers of early HCC detection.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Tumor growth and response to therapy, particularly immunotherapy, are all highly dependent on the tumor microenvironment (TME): the collection of cells and extracellular factors (cytokines, chemokines, collagens, etc.) that form around cancer cells. This is evident from the major impact drugs targeting TME components can have on cancers, including immune checkpoint blockade (ICB). Though there is a relatively good understanding of key genes regulating cancer cell intrinsic processes, such as cell cycle, there is less known about genes controlling the extrinsic environment that protects cancer cells from immunity and aids growth. The objective of this project is to determine the genes controlling tumor composition and facilitating tumor growth and resistance to immunity & immunotherapy, with the goal of identifying vulnerability factors that can be targeted to enhance tumor immunity and improve cancer treatment. The overarching hypothesis, which forms the rationale for this U01, is that malignant cells turn on or off genes, including intrinsically operating genes, through mutations and selective gene expression, that act extrinsically to recruit, position, & polarize immune & stroma cells into a state that subverts immunity & facilitates tumor growth1, 2. To reach our objective, we will employ a first-of-its-kind spatial functional genomics platform, called Perturb-map, which permits extensive phenotypic analysis of dozens of single or multiple gene perturbations in a tumor at single cell resolution and with spatial architecture preserved. With Perturb-map, CRISPR knockout (KO) or cDNA overexpression (OE) screens are resolved by multiplex imaging & spatial transcriptomics (ST), and this allows study of entire classes of genes (e.g. secreted factors) and phenotypes (e.g. TME composition) not feasible with existing screens. We will use Perturb-map to determine the role of 100s of genes in controlling many critical tumor processes, including tumor: (i) growth, (ii) morphology, (iii) metastasis, (iv) cell-cell interactions, (v) subclonal interactions, (vi) immune/stroma recruitment & polarization, (vii) resistance to immunotherapy & other treatments. The breadth & depth of analysis of each gene will be achieved at a scale and efficiency not previously feasible. We will focus on 3 broad categories of genes, identified through analysis of TCGA, ICB-treated cohorts, single cell-omics, and other patient data, including: commonly mutated cancer genes in solid tumors (Aim 1), genes correlating with resistance or response to ICB immunotherapy (Aim 2), and cancer cell-derived ligands and secreted molecules (Aim 3). Studies will be carried out in immunocompetent, orthotopic models of non-small cell lung carcinoma, high grade serous ovarian carcinoma, pancreatic adenocarcinoma, and oral squamous cell carcinoma. The study outcome will determine the roles of 100s of genes in many processes critical to unimpeded cancer growth, including identifying genes shielding cancers from immunity. In doing so, they will generate insights into mechanisms of aggressive tumor behavior and treatment resistance that will help to improve and personalize treatment selection and drive the immediate next steps towards the development of novel therapeutic strategies.

NIH Research Projects · FY 2025 · 2023-09

SUMMARY Long-term protection from viral infections is mediated by both the humoral and cellular immune pathways. Multiple Myeloma (MM) is the second most common hematological malignancy in the US and is characterized by clonal plasma cell production, resulting in immune suppression and recurrent bacterial and viral infections. SARS-CoV-2-specific antibody quantification are currently being used as clinical endpoints to determine immune protection against COVID-19, and this information is even more relevant in immunocompromised individuals who lack a humoral response, but are protected by the cellular immunity (i.e. MM patients). Despite the urgent need to quantify cellular immunity, the complexity and lack of scalability of traditional methods (e.g. ELISpot, flow cytometry) to detect antigen-specific T cells has so far prevented large scale studies. To address this problem, we developed a direct qPCR-based rapid T cell activation (dqTACT) assay based on ex vivo stimulation of whole blood samples with a pool of viral peptides (i.e.immunodominant peptides covering SARS-CoV-2 Spike protein), SARS-CoV-2 antigen-specific T cells, and CXCL10, followed by direct amplification of IFNG 𝛾 or IL2 which are produced by which is produced by monocytes and neutrophils in , response to T cell activation. The overarching aim of this proposal is to develop and implement a qPCR method that can be used as a proxy to measure the presence and functionality of antigen specific T cells in MM patients. Specifically, we hypothesize that SARS-CoV-2 specific T cells might be a biomarker of previous infection and of efficacy of vaccination strategies, complementary to quantification of the humoral response. In the UH2 phase, we will define analytical sensitivity and specificity and establish cut-off/thresholds and appropriate positive and quality controls, accuracy and false result rate by comparing the dqTACT assay with the gold standard assays such as flow cytometry and ELISpot for measuring cellular immune responses. In the UH3 phase, we will test the presence and persistence of cellular immunity to SARS-CoV-2 in convalescent and vaccinated myeloma patients. Well annotated patient populations will be used to define sensitivity, specificity, and thresholds with response to clinical end-points, such as presence and persistence of humoral and cellular immunity to SARS-CoV-2. We will estimate the prevalence of the markers within vaccinated myeloma patients. We will then extend our studies and use banked as well as fresh samples from our large myeloma/immunocompromised population and healthy controls enrolled in IRB approved studies. The overarching goal is to use the dqTACT assay to test the presence of T cells due to natural infection or vaccination in myeloma patients, possibly aiding in nationwide booster strategies or passive antibody infusion support to protect these vulnerable population. Key deliverables an assay to rapidly quantify the functionality of T cellular immunity at scale.

NIH Research Projects · FY 2025 · 2023-09

Abstract The NIH Common Fund (CF) programs have produced transformative datasets, databases, methods, bioinformatics tools and workflows that are significantly advancing biomedical research in the United States and worldwide. Currently, CF programs are mostly isolated. However, integrating data from across CF programs has the potential for synergistic discoveries. In addition, since CF programs have a time limit of 10 years, sustainability of the widely used CF digital resources after the programs expire is critical. To address these challenges, the NIH established the Common Fund Data Ecosystem (CFDE) program which has been recently approved to continue to its second new phase. For the second phase of the CFDE, this project will establish the Data Resource Center (DRC) and the Knowledge Center (KC). Our efforts will culminate in producing The CFDE Workbench which will be composed of three main products: the CFDE information portal, the CFDE data resource portal, and the CFDE knowledge portal. These three web portals will be full-stack web-based applications with a backend database and will be integrated into one public site. The CFDE information portal will be the entry point to the other two portals. It will contain information about the CFDE in a dedicated About page, information about each participating and non-participating CF program, information about each data coordination center (DCC), a link to a catalog of CF datasets, and a link to a catalog of CF tools and workflows, news, events, funding opportunities, standards and protocols, educational programs and opportunities, social media feeds, and publications. The CFDE data resource portal will contain metadata, data, workflows, and tools which are the products of the CF programs, and their data coordination centers (DDCs). We will adopt the C2M2 data model for storing information about metadata describing DCC datasets. We will also archive relatively small omics datasets that do not have a home in widely established repositories and do not require PHI protection. In addition, we will expand the cataloging to CF tools, APIs, and workflows. Importantly, we will develop a search engine that will index and present results from all these assembled digital assets. In addition, continuing the work established in the CFDE pilot phase, users of the data portal will be able to fetch identified datasets through links provided by the DCCs via the DRS protocol. This will include links to raw and processed data. The CFDE knowledge portal will provide access to CF programs processed data in various formats including: 1) knowledge graph assertions; 2) gene, drug, metabolite, and other set libraries; 3) data matrices ready for machine learning and other AI applications; 4) signatures; and 5) bipartite graphs. In addition, the extract, transform, and load (ETL) scripts to process the data into these formats will be provided. Since such processed data is relatively small, we will archive and serve this processed data, mint it with unique IDs, and serve it via APIs. In addition, we will develop workflows that will demonstrate how the processed data can be harmonized. At the same time, we will document APIs from all CF DCCs and provide example Jupyter Notebooks that demonstrate how these datasets can be accessed, processed, and combined for integrative omics analysis. For the knowledge portal we will also develop a library of tools that utilize these processed datasets. These tools will have some uniform requirements enabling a plug-and-play architecture. To achieve these goals, we will work collaboratively with the other CFDE newly established centers, the participating CFDE DCCs, the CFDE NIH team, and relevant external entities and potential consumers of these three software products. These interactions will be achieved via face-to-face meetings, virtual working groups meeting, one-on-one meetings, Slack, GitHub, project management software, and e-mail exchange. Via these interactions, we will establish standards, workstreams, feedback and mini projects towards accomplishing the goal of developing a lively and productive Common Fund Data Ecosystem.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY Temporal lobe epilepsy (TLE) is a debilitating disorder characterized by spontaneous and recurring seizures as well as pervasive memory and psychiatric impairments. These TLE-induced comorbidities do not respond to pharmacological treatment, and little is known about how specific brain circuits are altered by disease to drive these clinical phenotypes. Recent evidence suggests that these comorbidities are driven by deficits along the dorsoventral axis of the entorhinal-hippocampal circuit and that they are dissociable from seizures themselves. As such, it is imperative to study how epilepsy may detrimentally alter temporal lobe circuitry that is a key node in memory and emotion processing. In previous work, our lab and others have established CA1 of dorsal hippocampus (dCA1) as a site of poor spatial processing in epileptic mice. However, it remains unclear if upstream inputs to dCA1 are impaired which may be driving downstream changes in hippocampus. In the F99 phase, I will test the hypothesis that medial entorhinal cortex (MEC) has disrupted spatial coding in epileptic mice and will specifically test how distinct hippocampal inputs from layer 3 (MECIII) pyramidal neurons and layer 2 (MECII) stellate cells are altered. I will perform in vivo calcium imaging in these isolated subpopulations as epileptic and control mice perform spatial foraging and memory tasks, both before and after the onset of progressive memory impairments. This will allow me to determine the relationship between these spatial coding metrics and progressive memory deficits found in epileptic mice. During this phase I will receive technical training on in vivo calcium imaging and large-scale data analysis, as well as conceptual training on epilepsy models, learning and memory circuits, spatial coding, and integrating neural recordings with behavior. In the K00 phase, I plan to combine my previous expertise in stress-induced changes in entorhinal- hippocampal signaling with my current work in epilepsy circuits to determine how the ventral extent of this circuit contributes to altered emotional regulation in epilepsy. I will combine state-of-the-art mouse behavior, molecular assays, gene expression studies, calcium imaging, and virally mediated manipulation techniques to characterize ventral entorhinal-hippocampal circuit changes that drive psychiatric symptoms in epilepsy. Results from these studies will provide new insights into the neural and circuit mechanisms of epilepsy induced emotion deficits. Together, this training across F99 and K00 phases will support my successful transition to postdoctoral researcher and ultimately a career as an independent research scientist focusing on molecular, cellular, behavioral, and circuit-level signatures of behavioral dysfunction associated with epilepsy and stress.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY The older Asian American population has been rising, with the risk of Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD) also increasing. However, most of the disparities in health outcomes are masked because older Asian Americans are significantly underrepresented in clinical research. Social determinants of health (SDOH) are an individual’s personal circumstances that influence their health and well- being. SDOH contribute to wide health disparities and inequities. Research linking AD/ADRD to SDOH is expanding rapidly, yet much evidence is still needed in older Asian Americans. Additionally, there are relatively few studies incorporating health related risks, such as vascular conditions, and biomarkers to understand the link between SDOH and AD/ADRD; it remains unclear if vascular risk factors and/or biomarkers mediate such a relationship. Using validated cognitive tests in English/Chinese and culturally relevant measures of sociodemographic factors, the study MPI (Li) successfully enrolled over 200 older Asian Americans in clinical research at the Alzheimer’s Disease Research Center (ADRC) at Mount Sinai. Here, the study team will grow to include multidisciplinary members, proposing a 5-year study to develop a research infrastructure for studying AD/ADRD in older Asian Americans. The SDOH assessment will be available in English, Mandarin, and Cantonese – the most common spoken languages among Asian American older adults. This study will answer the following questions: (1) Do Chinese translation and cultural adaptation of SDOH measures effectively recruit new and existing older Asian Americans in AD/ADRD research? (2) Can we identify behavior, environmental, social, genetic, and neurobiological factors associated with AD/ADRD? (3) How neurobiological processes intersect with environmental, sociocultural, behavioral, and other demographic factors to affect AD/ADRD outcomes? The study team will establish a scientific advisory board to provide scientific perspectives for the proposed study, particularly in the areas of (1) Social science; (2) Clinical phenotypes of AD/ADRD; (3) Dementia research in Asian Americans; and (4) Risk factors and biomarkers for AD/ADRD. The team will also collaborate with key community stakeholders to ensure that the SDOH assessment is culturally and linguistically appropriate. Recruitment goal is set to be 300 older Asian Americans to complete a comprehensive dementia evaluation that includes SDOH measurement. Novel, theory based SDOH indices will be developed to characterize older Asian Americans in the normal, MCI, and AD/ADRD groups. Of the 300 enrollees, the study team aims to re-evaluate 100 participants for a 1-year follow-up and collect 200 biomarker samples for molecular profiling, including whole genome sequencing, RNA-sequencing and proteomics. An integrative network biology and machine learning based approach will be employed to develop highly predictive diagnostic and prognostic molecular biomarkers of AD/ADRD. The UH2 phase will be used to develop the research infrastructure and assessment tools necessary to apply for a larger RO1 project at the end of the UH3 phase.

NIH Research Projects · FY 2025 · 2023-09

The key appeal of polygenic risk scores (PRS) is the provision of individual-level estimates of genetic liability to complex disease. These proxies of genetic liability enable a raft of applications across clinical and basic research settings. However, while PRS are set to play a pivotal role in the future of biomedical research, their present formulation is suboptimal for application across the multi-ancestry US population. To address this, we propose to develop high-resolution modeling to optimize the computation of PRSs across the multi-ancestry US population, which will: (i) use Bayesian hierarchical modeling to account for the population genetic and statistical causes of low PRS portability between populations, (ii) deconstruct genetic risk into shared, ancestry-focused and gene*environment sub-components, (iii) produce pathway-based PRSs that can help expose the functional causes of the portability problem and explain disease heterogeneity. The key deliverable will be the production of a powerful PRS suite of tools tailored to the multi-ancestry US population. The rationale is that failure to model important structural features that are inherent to clinical populations constitutes a vital loss of information. By modeling this high-resolution data in statistically principled and rigorous ways, researchers will be better placed to perform powerful PRS prediction in all individuals. This will offer unprecedented predictive power and insights into disease mechanisms. In Aim 1, we develop a Bayesian hierarchical PRS method, BridgePRS8, that models differences in LD, effect sizes and allele frequencies between and within ancestries. In Aim 2, we build a novel method, admixPRS, for application to genetically heterogeneous individuals that deconstructs the genome into local ancestry tracts, accounting for known demographic history, and decomposes genetic risk into 3 sub-components. In Aim 3, we develop a pathway-based PRS method for genetically heterogenous populations, PRSet+. Finally, we develop a unifying PRS method, globalPRS, that is powered to calculate PRS in any individual of the US population. Our proposal is significant because the burgeoning application of PRS means that increasing PRS portability will have immediate, high impact across the entire US population. By performing high-resolution modeling to boost PRS predictive power by mirroring the structure of human populations, and exposing gene*environment and pathway-level contributions to the PRS portability problem, our suite of PRS tools have the potential to increase the clinical utility of PRS and our understanding of how genetic risk varies across clinical populations. Our proposal is innovative because we develop the first Bayesian hierarchical PRS tools tailored to model the genetically heterogenous US population, in relation to: ancestry, genetic risk (3-component model), the genome (pathway-level PRS) and phenotype (sub-types). In summary, our proposal will deliver a suite of tools to the field to perform powerful PRS analyses across the US population and to better understand heterogeneity of disease and PRS.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT Pulmonary arterial hypertension continues to be a devastating chronic disease. Despite a variety of new therapies, this disease process remains highly morbid and fatal. Most therapies are only temporizing and are minimally effective because of the insidious onset and late recognition of this disease process. Double lung transplantation is the only effective treatment; however, because of scarcity of organs and listing inequities, most patients are unlikely to receive a transplant while on the waiting list. Developing an effective long-term support system that can offload the right ventricle and protect the pulmonary vasculature would provide a bridge of support and potential for recovery or management on pharmacological support. The objective and long-term goal of this project is to design a catheter that will eventually be coupled with a pulmonary support system that can prolong the survival and enhance the ability to medically treat patients with pulmonary artery hypertension, as well as provide a chance for those on the lung transplant waiting list to receive an organ. We intend to accomplish this by developing an innovative dual lumen catheter that can be positioned and fixed for a prolonged period of time using a novel engineering mechanism and will properly unload the right ventricle and pulmonary vasculature via an inter-atrial configuration. This will further include an innovative monitoring system to monitor and control flows and protect a deconditioned left ventricle, preventing left sided heart failure.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Alzheimer’s disease (AD), the most prevalent dementia, has no effective disease-modifying therapeutics. Our recent studies have linked abnormalities in lysine methyltransferases G9a/GLP (also known as EHMT2/1) and histone H3 lysine 9 dimethylation (H3K9me2) to AD pathophysiology. We hypothesize that pharmacological inhibition of G9a and GLP by small molecules can provide a novel and effective therapeutic strategy for the treatment of AD. The objectives of this project are: (a) to demonstrate that newly-discovered G9a/GLP inhibitors are efficacious in AD mouse models; (b) to optimize small-molecule inhibitors of G9a and GLP into a drug candidate. To achieve these goals, we will pursue three specific aims. Aim 1, assess selectivity, cellular activity and in vitro ADME (absorption, distribution, metabolism and excretion) and in vivo pharmacokinetic (PK) properties of lead G9a/GLP inhibitors; Aim 2, evaluate in vivo effects of lead G9a/GLP inhibitors on normalizing behavioral, synaptic, and transcriptional abnormalities in AD mouse models; Aim 3, Optimize current G9a/GLP inhibitor leads into a drug candidate by designing, synthesizing and testing novel compounds to simultaneously optimize potency, selectivity and PK properties. Completion of the proposed studies will not only validate our therapeutic hypothesis, but also generate a drug candidate that could be ultimately translated in the clinic for the treatment of AD. The improved G9a/GLP inhibitors generated in this project will also be invaluable chemical tools for assessing the therapeutic potential of G9a/GLP inhibition in other diseases.

NIH Research Projects · FY 2024 · 2023-09

Project Summary The older Chinese American population has been rising for the last few decades, with the risk of Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD) also increasing. Despite the pressing need to increase racial/ethnic diversity in clinical trial participation in the US, older Chinese Americans remain historically underrepresented and understudied in AD/ADRD research due to a lack of culturally and linguistically appropriate study materials and assessment tools. Using Chinese language translations of clinical measures and cognitive tests, the study PI (Li) successfully enrolled over 200 older Chinese Americans in clinical research at the Alzheimer’s Disease Research Center (ADRC) at Mount Sinai. The sample, with over 80% non-demented older adults, provides a window of opportunity for early intervention and treatment of AD/ADRD. Since a majority of older Chinese Americans are foreign born with limited to no English proficiency, they are frequently excluded from clinical trial participation as English language proficiency is one of the inclusionary criteria. The Memory Support System (MSS) from the Healthy Action to Benefit Independence & Thinking® (HABIT) Program is a promising non-pharmacological intervention for Mild Cognitive Impairment (MCI). Prior data suggest the effectiveness of MSS on self-efficacy for memory, adapted functioning, quality of life, depression, and anxiety in the participants and their study partners, with an excellent retention rate. However, the MSS was primarily developed and used on non-Hispanic White, English-speaking adults. Additionally, little is known regarding the effectiveness of MSS on cognitive and neuropsychiatric symptoms associated with early AD/ADRD. Here, the study team proposes a 2-year study to translate and adapt the MSS materials and assessment tools from English into Mandarin and Cantonese - the most common spoken languages in the US after English and Spanish. This study will leverage Dr. Li’s expertise in research recruitment and enrollment of Chinese American older adults to answer the following questions: 1) Does Chinese language translation and cultural adaptation of MSS effectively engage and recruit Chinese Americans in clinical trials for AD/ADRD? (2) Can Chinese Americans with MCI and their study partners learn and use the MSS? (3) Is the MSS effective in mitigating early symptoms of AD/ADRD in older Chinese Americans? The team will collaborate with key community stakeholders to ensure that the materials and tests are culturally and linguistically appropriate for this population. Capitalizing on the older Chinese American cohort at the ADRC at Mount Sinai, the overarching goal is to extend the MSS to older Chinese Americans with MCI by developing a linguistically and culturally appropriate adaption. Using 30 Mandarin- and 30 Cantonese-speaking older adults with MCI and their study partners, the primary outcomes are recruitment, retention, and completion rates to assess feasibility. The team will also examine the efficacy and utility of MSS in this sample. Findings from this study will provide pilot data to support a large-scale clinical trial with longer follow-up periods.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY The older Asian American population has been rising, with the risk of Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD) also increasing. However, most of the disparities in health outcomes are masked because older Asian Americans are significantly underrepresented in clinical research. Social determinants of health (SDOH) are an individual’s personal circumstances that influence their health and well- being. SDOH contribute to wide health disparities and inequities. Research linking AD/ADRD to SDOH is expanding rapidly, yet much evidence is still needed in older Asian Americans. Additionally, there are relatively few studies incorporating health related risks, such as vascular conditions, and biomarkers to understand the link between SDOH and AD/ADRD; it remains unclear if vascular risk factors and/or biomarkers mediate such a relationship. Using validated cognitive tests in English/Chinese and culturally relevant measures of sociodemographic factors, the study MPI (Li) successfully enrolled over 200 older Asian Americans in clinical research at the Alzheimer’s Disease Research Center (ADRC) at Mount Sinai. Here, the study team will grow to include multidisciplinary members, proposing a 5-year study to develop a research infrastructure for studying AD/ADRD in older Asian Americans. The SDOH assessment will be available in English, Mandarin, and Cantonese – the most common spoken languages among Asian American older adults. This study will answer the following questions: (1) Do Chinese translation and cultural adaptation of SDOH measures effectively recruit new and existing older Asian Americans in AD/ADRD research? (2) Can we identify behavior, environmental, social, genetic, and neurobiological factors associated with AD/ADRD? (3) How neurobiological processes intersect with environmental, sociocultural, behavioral, and other demographic factors to affect AD/ADRD outcomes? The study team will establish a scientific advisory board to provide scientific perspectives for the proposed study, particularly in the areas of (1) Social science; (2) Clinical phenotypes of AD/ADRD; (3) Dementia research in Asian Americans; and (4) Risk factors and biomarkers for AD/ADRD. The team will also collaborate with key community stakeholders to ensure that the SDOH assessment is culturally and linguistically appropriate. Recruitment goal is set to be 300 older Asian Americans to complete a comprehensive dementia evaluation that includes SDOH measurement. Novel, theory based SDOH indices will be developed to characterize older Asian Americans in the normal, MCI, and AD/ADRD groups. Of the 300 enrollees, the study team aims to re-evaluate 100 participants for a 1-year follow-up and collect 200 biomarker samples for molecular profiling, including whole genome sequencing, RNA-sequencing and proteomics. An integrative network biology and machine learning based approach will be employed to develop highly predictive diagnostic and prognostic molecular biomarkers of AD/ADRD. The UH2 phase will be used to develop the research infrastructure and assessment tools necessary to apply for a larger RO1 project at the end of the UH3 phase.

NIH Research Projects · FY 2024 · 2023-09

Project Summary Deep brain stimulation (DBS) targeting white matter instead of specific nuclei or cortex is an emerging therapeutic approach for individuals with treatment resistant neurological or psychiatric disorders. This treatment approach is thought to have its beneficial effects through functional modulation of neural activity across distributed brain networks that connect through the white matter that is being stimulated. Evidence for this is, however, in short supply. This means that the underlying functional and anatomical mechanisms that contribute to the therapeutic effects of white matter DBS are poorly understood. Lack of this knowledge hinders refinement of this treatment and its potential use to target other white matter tracts. Here we will model the effects of DBS in macaques and determine the mechanisms engaged by DBS therapy that targets the location where three white matter tracts – forceps minor, uncinate fascicle and cingulum bundle – overlap in frontal cortex adjacent to subcallosal anterior cingulate cortex (ACC). We will employ this model as prior work has shown that stimulation of these tracts is associated with both fast positive changes in affect as well as slower longer-term effects on affective state that develop over many weeks in people with treatment resistant mood disorders. Our aim here is to establish the micro- and meso-scale neurological changes across both time frames caused by deep brain stimulation. We hypothesize that they are caused by two distinct mechanisms. The fast effects are the result of functional changes whereas the slow changes are the result of structural changes to white matter. To test our hypothesis, we will use a combination of deep brain stimulation, resting-state fMRI, neurophysiology, and postmortem anatomy in macaque monkeys. Using the same diffusion imaging tractography approach used in human patients, mini-deep brain stimulation electrodes will be targeted to the confluence of three white matter tracts. We will then assess the progressive systems level changes in fMRI resting-state functional connectivity and diffusion weighted imaging estimates of anatomical connections that are caused by deep brain stimulation of these three white matter tracts. In parallel, we will assess the microscale neurophysiological changes that occur as a result of stimulation. Here our experiments are designed to discern the immediate effects of stimulation on functional interaction between areas that directly connect through the white matter adjacent to subcallosal ACC as well as the longer-term changes in functional communication between areas. Finally, we will characterize the changes in anatomy that are associated with the brain-wide functional effects of deep brain stimulation to white matter. Here we will use both confocal and electron microscopy to discern alterations to white matter that are caused by stimulation. Completing these experiments will begin to reveal the functional and anatomical mechanisms of DBS when it is directed to white matter. Overall, what we discover will provide insights into how circuit-level functions are modulated by DBS as well as aid the refinement of emerging DBS treatments.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Deep brain stimulation (DBS) targeting white matter instead of specific nuclei or cortex is an emerging therapeutic approach for individuals with treatment resistant neurological or psychiatric disorders. This treatment approach is thought to have its beneficial effects through functional modulation of neural activity across distributed brain networks that connect through the white matter that is being stimulated. Evidence for this is, however, in short supply. This means that the underlying functional and anatomical mechanisms that contribute to the therapeutic effects of white matter DBS are poorly understood. Lack of this knowledge hinders refinement of this treatment and its potential use to target other white matter tracts. Here we will model the effects of DBS in macaques and determine the mechanisms engaged by DBS therapy that targets the location where three white matter tracts – forceps minor, uncinate fascicle and cingulum bundle – overlap in frontal cortex adjacent to subcallosal anterior cingulate cortex (ACC). We will employ this model as prior work has shown that stimulation of these tracts is associated with both fast positive changes in affect as well as slower longer-term effects on affective state that develop over many weeks in people with treatment resistant mood disorders. Our aim here is to establish the micro- and meso-scale neurological changes across both time frames caused by deep brain stimulation. We hypothesize that they are caused by two distinct mechanisms. The fast effects are the result of functional changes whereas the slow changes are the result of structural changes to white matter. To test our hypothesis, we will use a combination of deep brain stimulation, resting-state fMRI, neurophysiology, and postmortem anatomy in macaque monkeys. Using the same diffusion imaging tractography approach used in human patients, mini-deep brain stimulation electrodes will be targeted to the confluence of three white matter tracts. We will then assess the progressive systems level changes in fMRI resting-state functional connectivity and diffusion weighted imaging estimates of anatomical connections that are caused by deep brain stimulation of these three white matter tracts. In parallel, we will assess the microscale neurophysiological changes that occur as a result of stimulation. Here our experiments are designed to discern the immediate effects of stimulation on functional interaction between areas that directly connect through the white matter adjacent to subcallosal ACC as well as the longer-term changes in functional communication between areas. Finally, we will characterize the changes in anatomy that are associated with the brain-wide functional effects of deep brain stimulation to white matter. Here we will use both confocal and electron microscopy to discern alterations to white matter that are caused by stimulation. Completing these experiments will begin to reveal the functional and anatomical mechanisms of DBS when it is directed to white matter. Overall, what we discover will provide insights into how circuit-level functions are modulated by DBS as well as aid the refinement of emerging DBS treatments.

NIH Research Projects · FY 2026 · 2023-09

While most ovarian cancer (OvCa) patients initially respond to surgery and chemotherapy, over 80% of these patients eventually develop recurrent tumors, most commonly in the peritoneal cavity. These recurrent tumors exhibit resistance to chemotherapy and often show poor responses to immunotherapy, which makes OvCa one of the hardest cancers to treat lacking effective second-line therapies. Recurrent tumors with high mutation burden and in elder patients are associated with an immunosuppressive tumor microenvironment (TME), which may contribute to the limited benefit of immunotherapy, such as immune checkpoint blockade (ICB). However, the mechanisms by which tumor-intrinsic genetic alterations and host aging reprogram the TME remain largely unknown due to the lack of high-throughput functional genomic screening methods to perturb tumor genes. This proposal seeks to address this gap and expand our knowledge of the tumor gene regulation of the TME by employing Perturb-map, a novel spatial functional genomics platform. With Perturb-map, we will be able to analyze the phenotypic effects of multiple gene perturbations in OvCa at single-cell resolution while preserving the spatial architecture of tumors and their TME. In Aim 1, we will define cancer-intrinsic mutations that mediate recurrence via reprograming the TME. We will perform Perturb-map screening for OvCa-associated genes with known or suspected roles in modulate TME with a focus on immunosuppressive myeloid cells. We will use the immunization protocol, previously developed in the F99 phase, to model tumor recurrence in a host that have had the primary tumor treated, closely mimicking adaptive immune response in patients with recurrent disease. By comparing tumors with different genetic perturbation, such as knockouts (KO), we will identify genes and factors that regulate TME. We will determine if the tumor-intrinsic immunosuppressive factors can be targeted to restore immune competence and improve ICB response. Advanced aging is the top risk factor for cancer overall and for specific metastatic cancer types including OvCa. Aging-associated senescence in host cells, such as immune cells, can lead to altered immune cells distributions and effector function resulting in an immunosuppressive TME. Cancer cells can also undergo senescence program featured by a senescence-associated secretory phenotype (SASP) which is also immunosuppressive. In Aim 2, we will investigate how age-associated factors influence the cancer cells and senescent cancer cell to suppress TME in aged host, promoting immune evasion and recurrence. We will utilize the Perturb-map technology to identify SASP factors critical for TME reprogramming. Additionally, we will test senolytic therapies or targeting agents to determine whether the senescence cells or the SASP factors can be targeted to improve immunotherapy response in the elderly patients. Ultimately, this research will identify novel therapeutic targets to develop tailored strategies for patients with immunosuppression due to specific mutations and advanced aging, enhancing immunotherapy responses and improving survival outcomes.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY How does decision-making influence memory to leave a long-lasting impact on human behavior? Answering this question is critical to understanding how impaired decision making might lead to maladaptive memory outcomes, such as rumination on negative events, susceptibility to false memories, or memory loss. In recent years, the reinforcement learning (RL) framework has been particularly fruitful for describing impaired decision-making in psychiatric disorders as well as identifying computational mechanisms linking decision-making and memory. The overarching aim of this project is to identify the neurocomputational mechanisms that explain how the learning processes driving decision-making also influence subsequent memory. To do so, the K99 phase of the proposed study consists of a computational approach to identify how model-free reinforcement learning signals influence both hippocampal and non-hippocampal recognition memory performance in humans (Aim 1), and a neurobiolog- ical approach to identify the electrophysiological mechanisms underlying these RL-memory interactions (Aim 2); the R00 phase of the study will deploy these approaches to study the contributions of model-based reinforcement learning to these distinct memory processes (Aim 3). Specifically, Aim 1 will test how model-free RL signals such as prediction errors might interact with the perceptual features of a stimulus to enhance both immediate (non- hippocampal) memory and delayed (hippocampal) memory in healthy volunteers. Aim 2 will leverage intracranial recording obtained from humans with epilepsy monitoring electrodes to test how neural activity in the frontal cor- tex, hippocampus, and non-hippocampal medial temporal regions (such as parahippocampal gyrus) subserve the influence of model-free RL processes on memory performance. Upon completion of Aims 1-2 (K99), the candidate—a neuroscientist with a background in the neurobiology of human memory—will obtain new training in computational modeling of reinforcement learning and decision-making and have a unique, multi-disciplinary skillset to apply to Aim 3 (R00), to study how model-based RL processes influence mnemonic behavior and neural activity. The candidate’s mentors are uniquely suited to provide the training for these Aims, given their expertise in bridging computational modeling (Dr. Xiaosi Gu) and human neurophysiology (Dr. Ignacio Saez) to understand human decision-making. These skills will also facilitate the candidate’s transition into an independent researcher with the long-term goal of performing integrative behavioral, computational, and biological studies of how these human decision-making and memory processes go awry in psychiatric disorders.

NIH Research Projects · FY 2024 · 2023-09

Project Summary/Abstract Underage drinking in the US is a serious public health concern. Early onset of alcohol use (<15 years old), increases the risk of developing alcohol use disorder by seven times compared to those who start drinking later. Therefore, a comprehensive understanding of biopsychosocial factors associated with early alcohol use onset in adolescence is crucial to address this problem. To this end, extensive studies have been conducted and have identified genetic factors linked to future alcohol use, such as family history of alcoholism and higher polygenic liability. The limited scope of genetic studies poses significant challenges including the (1) primary inclusion of participants of European ancestry, (2) exclusion of those in the early stages of alcohol use, and (3) unclear clinical applicability. This necessitates the need for exploring non-genetic environmental exposures (i.e., exposome) associated with alcohol use onset. As such, the proposed study aims to leverage data from the highly powered and nationally diverse cohort, the Adolescent Brain Cognitive Development Study (ABCD; n = 11,000, 9-10-year-olds), and use a novel eXposome-Wide Association Studies (XWAS) approach to identify exposomic risk factors and derive PolyeXposure Alcohol Risk Scores (PXARS) for alcohol use onset in adolescents up to age 14. The performance of PXARS will be benchmarked against these established genetic risk factors. Furthermore, the risk for alcohol use onset is linked to poor inhibitory control; thus, this proposed project will comprehensively examine the neurobiological and behavioral correlates of prospective alcohol use onset using data from the Stop Signal Task (SST). Studies also suggest that exposomic factors may influence inhibitory control development; therefore, this study aims to uncover associations between neurobehavioral factors, PXARS, and alcohol use onset. Unlike studying the genome, examining the exposome allows for investigating the totality of the environment (i.e., natural, built, and social) to uncover potentially clinically actionable targets. While many exposomic predictors may not be easily modifiable (e.g., racial biases, socioeconomic barriers) but still warrant close examination; other predictors (e.g., peers, diet, and activities) may be viable prevention and intervention targets for preventing and minimizing alcohol use in youth. The proposed study offers the applicant a robust and comprehensive training program, which includes in-depth instruction on big data and bioinformatics approaches, as well as task-based fMRI techniques and will significantly strengthen the applicant's skillset. The applicant will receive exceptional support from a team of highly skilled sponsors and consultants who have extensive experience in the fields of substance use neurobiology, exposomics, and neuroimaging. Furthermore, the research will be conducted at the Icahn School of Medicine, a world-renowned institution that offers top-tier training, coursework, and institutional resources including but not limited to the Addiction Institute, the Institute for Exposomic Research, and the High-Performance Computing Core, making it an ideal setting for executing the proposed study.

NIH Research Projects · FY 2025 · 2023-09

We aim to increase students' understanding and interest in science through active participation in the first large-scale tracking initiative targeting avian viruses like influenza viruses and avian paramyxoviruses (also known as Newcastle disease virus) ever conducted in an urban area - New York City (NYC) - via analysis of bird droppings. The New York City Virus Hunters (NYCVH) initiative will enable teachers and students, to gain an understanding of the interaction of natural environments and human health while increasing their knowledge, confidence, and interest in science. The NYCVH initiative will build on strong collaborations between the Krammer Laboratory at the Icahn School of Medicine at Mount Sinai (ISMMS) and BioBus, a NYC science education institution. NYCVH will develop and provide all the training, equipment, materials, and infrastructure needed to support this research effort. NYCVH will be designed to offer multiple entry points and levels of engagement for interested students and teachers to participate. Trainings will ensure that interested teachers gain an understanding of modern tracking techniques for microbes and have ways to easily incorporate NYCVH program aspects of their choice into their work. Over the course of the program, 6,000 middle and high school students will be led by 100 teachers trained at workshops held at the BioBus’s BioBase. Workshops will introduce teachers to molecular techniques, experimental design, laboratory and bioinformatics methods, sampling kit components, and details on how teachers and students can participate in research to stay healthy and prevent future pandemics. Through the BioBus’ network, we will enlist partner schools to broaden participation in the program including school-based sampling events. In addition, and importantly, 25 local high school students will be trained to spearhead the initiative as Junior Research Scientists. These students will join the NYCVH as interns over the academic year and get intensive training in sampling, nucleic acid detection, sequencing, phylogenetic analysis, and virology in general to become the next generation of leading scientists. With ISMMS, BioBus and a network of scientists from academic institutions and wildlife rehabilitators, students will be supported throughout their research process, including but not limited to study design, sample collection, sample processing, data analysis, and research presentations. This project will be evaluated using a mixed-methods approach tailored to understanding the impact of program participation on all individuals. Leveraging participatory research, this program is structured to assess the feasibility of large-scale studies at the urban human–bird interface as well as the impact it has on shaping the students’ long-term STEM career aspirations.