Weill Medical Coll Of Cornell Univ

NIH Research Projects · FY 2026 · 2019-09

Abstract (30 lines): With the recent progress in structural biology, i.e., the cryo-EM `resolution revolution', solving protein structures has become quite straight-forward. Importantly, the cryo-EM resolution revolution in structural biology, resonating the transformation that super-resolution fluorescence microscopies brought to cell biology, highlights how technical advances do not provide incremental progress but have the power to transform entire fields. In this project, we will transform high-speed atomic force microscopy (HS-AFM). HS-AFM is already capable to deliver movies of biomolecules at 1 to 20 frames per second, depending on the imaging size. Here, in Aim 1 we redesign the x-, y-scanner to feature two equal high-speed piezos, which will not only grant improved scan motion at high speed, but, importantly, enable HS-AFM circular scanning (HS-AFM-CS) to probe the conformational state of multiple subunits within an oligomer. As HS-AFM-CS probes the conformational state of the protomers in an oligomer at a time interval of only ~16µs, we can study conformational cooperativity between subunits. In Aim 2 we adapt 3D-AFM for the study of water- and ion- layers on protein surfaces. When oscillating the AFM-tip at Angstrom amplitude while approaching it to a surface, the AFM-tip senses the resistance of organized water- and ion- layers in the proximity of surfaces, reported by oscillation amplitude and phase changes. This potential of AFM remains quasi-unexploited in biology, despite the need to understand how proteins interact with and modulate their bulk environment. Finally, in Aim 3 we develop a next generation HS-AFM (NG-HS-AFM) with substantially increased sensitivity and imaging speed. To achieve this goal, we redesign the AFM-laser optical path, and, taking advantage of a cleaner signal from the cantilever, we drive two z-piezos via a newly designed dual-feedback operation. A faster z-piezo will contour the fine details on the protein surfaces, while a slower z- piezo compensates for the global molecular shape. The dual-feedback operated NG-HS-AFM will allow protein imaging at 100 frames per second. None of the project axes depends on the success of the others, but HS-AFM- CS (Aim 1) and 3D-AFM (Aim 2) will naturally be integrated in the NG-HS-AFM (Aim 3). Together, these developments establish HS-AFM as a unique technique to measure protein dynamics at unprecedented detail and speed. We will exploit the NG-HS-AFM to image odorant receptor-channel dynamics at 10 millisecond temporal resolution and quasi-atomic resolution. HS-AFM-CS will be used to measure the conformational cooperativity between subunits at ~16 microsecond temporal resolution, and 3D-AFM to assess the interaction with water and ions. Our developments will be bench-market using well-studied transporters, e.g., bR and GltPh, and channels, e.g., AqpZ and KcsA. Importantly, our developments are generally applicable, and while our work will provide invaluable new insights into the biological systems under investigation, the major aim of this application is to develop new technology that will further the dynamic analysis of biomolecules in general.

NIH Research Projects · FY 2025 · 2019-09

OVERALL ABSTRACT The Partnership Center, entitled Multinational Partnership to Prevent HPV-Associated Cancer in People Living with HIV: Brazil, Mexico, Puerto Rico (PHAC-BMPR), will bring together experienced research sites and world- renowned HPV and HIV researchers to build on established collaborations to conduct clinical trials on prevention of HPV-associated cancers among people living with HIV. This will provide an invaluable opportunity for newer investigators from Latin America/Caribbean (LAC) to participate in and learn from high- quality research. PHAC-BMPR will focus on two HPV-associated cancers that result in substantial morbidity and mortality: HPV- associated oropharyngeal cancer (HPV-OPC) and cervical cancer. These scientific goals are aligned with the goals of the US National Institutes of Health for research priorities for people living with HIV/AIDS as well as in country and regional goals to reduce cancer morbidity and mortality. At the end of this project, we hope to make advances that will highly impact prevention of HPV-associated cancers in people living with HIV and contribute to the global goal of cervical cancer elimination and reduction of other HPV-associated cancers such as oropharyngeal cancer (OPC).

NIH Research Projects · FY 2025 · 2019-09

Project Summary/Abstract Binge alcohol drinking is a major risk factor for many diseases, including alcohol use disorder (AUD) and other neuropsychiatric diseases, and women are at greater risk for developing AUD than men with the same history of alcohol use. The sex hormone estrogen, which fluctuates across the menstrual/estrous cycle in females, has been implicated in playing a regulatory role in alcohol drinking behavior across mammalian species, but the specific mechanisms underlying this function are not well understood. We recently found that ovarian estrogen acts via rapid, nongenomic signaling at membrane-associated estrogen receptors in the limbic system to drive binge alcohol drinking behavior in gonadally intact female mice. We hypothesize that estrogen regulates presynaptic neurotransmitter release and postsynaptic excitability in a coordinated fashion to regulate the activation and signaling of critical neuropeptidergic circuits that promote alcohol use. In the proposed work, we examine the circuit and receptor signaling context for rapid E2 modulation of neuronal function that drives binge alcohol drinking in intact female mice. These studies will improve our understanding of this behavior in females, potentially providing new avenues for pharmacotherapeutic approaches to curbing excessive alcohol consumption.

NIH Research Projects · FY 2025 · 2019-09

Project Summary/Abstract Malaria control efforts are currently facing substantial challenges, primarily due to increasing drug resistance, including the first-line drugs artemisinins. From 2018 to 2021, there was a noticeable increase in new malaria cases, with the count rising from 237 million to 254 million, and the annual death toll surged from 567,000 to 617,000 in 2021. Over 90% of these cases and 96% of these deaths occurred in Sub-Saharan Africa, as reported by the World Health Organization (WHO). Tragically, 80% of the mortalities were children under the age of five. There is an urgent need for enhanced vector control measures and antimalarial drugs that are prophylactic, therapeutic, and transmission blocking. The proteasome plays a crucial role in regulating various cellular functions by degrading regulatory and damaged proteins. The proteasome is a well-established drug target for cancer treatment, with three FDA-approved drugs, and for certain infectious diseases, with two in clinical development. Malaria proteasome inhibitors have shown promise with killing activity against Plasmodium parasites at multiple stages of their life cycle, including the challenging transmission and liver stages. Therefore, a P. falciparum proteasome (Pf20S) inhibitor has potential to be a therapeutic, prophylactic, and transmission-blocking agent. Moreover, Pf20S inhibitors demonstrate synergistic effects when combined with artemisinins, making them even more appealing for malaria treatment. However, the development of orally bioavailable Pf20S inhibitors that can minimize the emergence of resistance while maintaining high selectivity for Pf20S over both the human constitutive proteasome and immunoproteasome presents a challenge. We have achieved significant progress in pursuit of these goals for antimalarial proteasome inhibitors. Furthermore, we have solved multiple cryo-EM structures of Pf20S with a β5 inhibitor, a β2 inhibitor, and a nonpeptide inhibitor, providing valuable insights into structure-activity relationships, mechanisms of resistance and collateral sensitivity. This application seeks to build upon these achievements by advancing our development program for both peptide-based and nonpeptide-based proteasome inhibitors, with a focus on enhancing potency, selectivity, and in vitro and in vivo pharmacokinetic properties to achieve oral bioavailability. We will conduct iterative structure-activity relationship (SAR) studies for both peptide- and nonpeptide-based Pf20S inhibitor series and assess their antimalarial activities at different parasite stages in vitro, as well as their parasitemia-reducing capabilities in animal models of malarial infection.

NIH Research Projects · FY 2026 · 2019-08

ABSTRACT Inositol pyrophosphates (IPPs) are signaling molecules involved in diverse cellular processes from telomere maintenance and apoptosis to vesicular trafficking and cell migration. Alterations in IPP levels (via mutations in IPP metabolizing enzymes) are linked to human pathology including cancer, obesity, diabetes and hearing loss. The pleiotropic effects suggest that inositol pyrophosphates have the ability to control very basic cellular functions. A role for IPPs in phosphate sensing and phosphate homeostasis is documented in fungi, plants, and humans. Cells respond to phosphate limitation by inducing the transcription of phosphate acquisition genes, yet the mechanisms by which this is achieved differ in each taxon. The phosphate (PHO) regulon in the fission yeast Schizosaccharomyces pombe comprises three genes that specify, respectively, a cell surface acid phosphatase Pho1, an inorganic phosphate transporter Pho84, and a glycerophosphate transporter Tgp1. Expression of pho1, pho84, and tgp1 is actively repressed during growth in phosphate-rich medium by RNA polymerase II (Pol2) transcription in cis of a long noncoding (lnc) RNA from the respective 5' flanking genes prt, prt2, and nc-tgp1. lncRNA transcription across the PHO mRNA promoter displaces the activating transcription factor Pho7 and thereby interferes with PHO mRNA expression. The system of lncRNA-mediated transcriptional interference is sensitive to genetic manipulations that influence 3’-processing/termination. Mutations that elicit “precocious” lncRNA 3'-processing/termination in response to poly(A) signals upstream of the mRNA promoters lead to de- repression of pho1, whereas genetic changes that diminish lncRNA termination hyper-repress pho1 expression. We have exploited this system to discover novel influences on 3’-processing and Pol2 termination. We showed that: (i) lncRNA transcription is subject to metabolite control by inositol pyrophosphate 1,5-IP8, which acts as an agonist of precocious 3'-processing/termination; (ii) Spx1, which is composed of an SPX domain and a RING E3 ligase domain, is a likely mediator of IP8 signaling to the 3'-processing/termination machinery; (iii) the 14-3-3 protein Rad24 antagonizes precocious 3’-processing/termination in a manner that depends on its phosphate binding site; and (iv) Pol2 termination can be enhanced via a gain-of-function mutation in the essential termination factor Seb1. Specific aims are: (1) to identify targets of the Spx1 E3 ubiquitin ligase (via TULIP2 tagging and mass spectrometry); and to test whether pyrophosphorylation of (or IP8 binding to) components of the Pol2 machinery contributes to the effects of IP8 on 3’-processing/termination; (2) to leverage new analytical methods to assess IPP abundance and isoform distribution in fission yeast strains where genetics predicts changes in IPP content, and to investigate whether and how phosphate starvation impacts cellular IPP content; (3) To probe the mechanism by which Rad24 antagonizes 3’-processing/termination, by performing ChIP-seq to identify genes with which Rad24 is associated in vivo; and (4) To generate new gain-of-function mutations in the essential termination factor Seb1 and analyze their effects on poly(A) site usage, RNA binding, CTD binding.

NIH Research Projects · FY 2025 · 2019-08

PROJECT SUMMARY/ABSTRACT Metabolomics has emerged as the newest systems-level discipline with demonstrated potential to provide mechanistic insights in the fields of infectious disease, microbiome science, inflammation, and immunology. However, a key barrier to this potential is the conceptually and technologically unique nature of metabolomics that distinguishes it from other systems level disciplines. This proposal seeks to continue to deliver and expand an established structured didactic and laboratory training program aimed at increasing both the conceptual and technological accessibility of metabolomics to NIAID-funded trainees. This program combines multiple educational activities tiered to maximize adoption and competence in advanced metabolomics techniques and equip trainees with both theoretical and practical understanding of these emerging technologies. This will be achieved through 3 complementary activities: Activity 1 is a didactic course accompanied by data analysis exercises developed to emphasize key concepts in both modern mass spectrometry, NMR analysis and the implementation of these approaches in biomedical research. In this renewal application, we will expand the mentored data analysis exercises and we will continue to refine and update this content to include emerging technologies and experimental approaches. Activity 2 is a mentored project development clinic aimed in which participants can develop ideas originating from their own research into actionable, well-controlled experiments – here, the emphasis is on recognizing the strengths and weaknesses of the available technologies, rigorous experimental design, and developing appropriate data analysis strategies. Activity 3 of the program consists of tailored, mentored laboratory research experiences allowing trainees to develop skills specifically aligned with their research objectives – this may constitute a series of small pilot experiments, the development or implementation of a new method, or refining an existing analytical strategy to better address their research question. Although these activities will frequently be accessed sequentially, our program will continue to support these modules being accessed independently. This further allows this program to deliver training, mentorship, and research experiences in a format that meets the individual trainee needs and their differing career stages. In this renewal application, we are also recruiting from NIAID-supported labs at all NY metro area research institutions to further expand the biomedical workforce in this discipline and will initiate a mechanism for disseminating program content via the existing online infrastructure at Cold Spring Harbor Laboratory.

NIH Research Projects · FY 2025 · 2019-07

ABSTRACT - OVERALL Congenital cytomegalovirus (cCMV) is a prevalent in utero infection, affecting approximately 1 in 200 newborns and leading to severe neurological impairment in 1 in 5 infected infants. Maternal CMV-specific adaptive immunity is partially protective against cCMV infection, with reduced transmission rates observed in chronically-infected women upon reinfection. However, challenges in CMV vaccine development include limited understanding of viral and immunological factors involved in cCMV transmission, strategies to counteract immune evasion mechanisms, and critical vaccine antigen targets. To address these challenges, our team developed and refined a nonhuman primate (NHP) model of cCMV infection in rhesus monkeys, which we demonstrated to closely mimic human transmission and fetal disease rates in our initial cycle of this P01 Program. Surprisingly, immune responses following maternal infection did not predict transmission risk, suggesting the need for pre-existing immunity different from natural infection. The NHP model also revealed T cell trafficking to the maternal-fetal interface following maternal CMV infection, the limited role of the viral pentameric glycoprotein complex in cCMV transmission, the role of Fc-mediated antibody responses in CMV containment, and viral immune evasion mechanisms as important factors in reducing CMV dissemination. Traditional vaccine approaches focused on neutralizing antibodies may be insufficient, prompting the evaluation of novel CMV vaccine candidates in the NHP model. We hypothesize that disarming the virus by eliciting immunity against key viral immune evasions and inducing cellular immunity at the maternal-fetal interface will prevent cCMV transmission following primary infection during pregnancy. The studies proposed in the renewal of this P01 Program will assess the role of CD8+ T cell responses at the maternal-fetal interface in preventing cCMV transmission (Project 1), the impact of vaccine-induced immunity against viral immune evasions, such as UL146 chemokine homologs (Project 2) and viral Fc receptors (Project 3), and test three novel vaccines targeting each of these novel immune mechanisms. The Program's ultimate goal is to develop an effective CMV vaccine, considering the limitations of previous approaches and targeting immune evasion proteins while eliciting local immunity at the maternal-fetal interface. The research will employ NHP models, placental organoid models, viral engineering, sequence analysis, and bioinformatics to de-risk these vaccine concepts before advancing to human efficacy trials. The successful development of a CMV vaccine is crucial for eliminating the most common infectious cause of birth defects and brain damage worldwide.

NIH Research Projects · FY 2025 · 2019-06

PROJECT ABSTRACT Uncontrolled inflammation in the gastrointestinal tract underlies the pathogenesis and progression of multiple chronic human diseases including allergy, hypersensitivity, inflammatory bowel disease (IBD), and graft- versus-host-disease (GVHD), and there is an urgent need to develop novel approaches to prevent, limit or reverse gut inflammation. The fundamental focus of our proposed renewal for R01AI145989 is to build on recent paradigm-shifting results from the first funding cycle defining that tissue resident lymphocytes shape the protective versus pathologic outcomes of key cytokines in gastrointestinal inflammation. Specifically, our prior studies detailed how group 3 innate lymphoid cells (ILC3s) drive immune tolerance and during homeostasis and inflammation by sensing and regulating key cytokine networks. We determined that ILC3s sense IL-23 to upregulate the immunoregulatory molecule, CTLA-4, which critically restrains gut inflammation (Ahmed et al., Nature, 2024). Further, we find that these cellular interactions are dysregulated in the inflamed intestine of individuals with IBD. These surprising data provoke the need to more broadly consider CTLA-4 biology beyond conventional T cells and in the context of distinct cytokine signals or microbial exposures. We generated new preliminary data to support this renewal application where we propose to mechanistically advance this paradigm. This includes two specific aims, which will define how specific tissue- resident innate and innate-like lymphocytes augment different types of immunity and inflammation in the intestine. We expect that our mechanistic results will provoke new opportunities for preventative, therapeutic or curative treatment strategies targeting chronic gut inflammation.

NIH Research Projects · FY 2026 · 2019-06

The overall goal of our research program is to understand the intricate mechanisms by which neurons establish the precise spatial and patterns of protein synthesis needed for synaptic plasticity and circuit formation. Much of this regulation occurs at the RNA level, and my laboratory focuses on uncovering novel regulatory mechanisms that enable this RNA-based control. Our research centers around three programs: (1) Epitranscriptomic regulation of neuronal mRNAs. We are often credited with helping to start a new field of RNA biology termed “epitranscriptomics,” the idea that mRNA fate and function is encoded in the RNA by regulatory nucleotide modifications. A major program in my lab focuses on epitranscriptomic regulation of mRNA fate in neurons by these modifications. (2) Deciphering the mechanism of RNA-directed epigenetic silencing in fragile X syndrome. We recently showed that fragile X syndrome is a disease caused by CGG repeat RNA. We found that this RNA forms a hybrid with complementary DNA to induce the epigenetic silencing, which constitutes a new epigenetic pathway. We are committed to understanding this new area of epigenetics and using knowledge of this pathway to develop a completely new approach to treat this major neurological condition. (3) Technologies for revealing the function of the synaptic transcriptome. In order to reveal new insights into RNA regulation in the brain, we develop novel technologies to enable imaging and analysis of mRNA, perhaps most notably “RNA mimics of GFP,” including Spinach. We will take these fluorogenic aptamers to the next level of brightness needed for the demanding imaging approaches used in live functioning animals. Additionally, we will be developing new engineered aptamers that enable light-control of synaptic mRNA translation. Overall, this research program will advance our understanding of post- transcriptional gene regulation in neurons.

NIH Research Projects · FY 2026 · 2019-05

Summary OVERALL; PD – Pascual, V. The Autoimmunity Center of Excellence based at Weill Cornell Medicine (WCM) in New York, NY aims at 1) advancing the knowledge of pathways and mechanisms that contribute to the development and amplification of Human Systemic Autoimmune Disease (SAD), and 2) developing tools and identifying biomarkers to monitor these dysfunctional pathways. Ultimately, we aim to be able to stratify patients towards personalized approaches to treatment. The Center will apply state-of-the-art technologies in immune profiling, cell biology and the field of nanoparticles to gain insight into disease contribution of two major and complementary compartments contributing to systemic disease: Immune Cells and Extra-Cellular Nanoparticles. The appropriate infrastructure is in place to support patient-based studies. In particular, we emphasize the following key conceptual and technological innovations adding to our strengths, that include access to an established pediatric SLE cohort followed by experienced clinical collaborators with an exceptional record of participation in translational research While the initial focus will be the study of children with Systemic Lupus Erythematosus (SLE), extrapolation of the Center findings to adult SLE as well as other SAD scenarios will be pursued, particularly in the context of the ACE Collaborative efforts. The Drukier Institute for Children’s Health Research at Weill Cornell Medicine has gathered a multidisciplinary team of pediatric basic and patient-oriented investigators with expertise in immunology, autoimmunity, cancer biology, molecular biology, and bioinformatics. This team works alongside clinical experts in autoimmunity, cancer, allergy and infectious diseases—bench-to-bedside and back—to understand and treat these diseases. The Institute and current WCM ACE investigators have also established strong local, national and international collaborations, many of whom are part of the larger ACE community. Dr. Pascual’s team has a long history of productive research in the fields of human autoinflammatory and autoimmune diseases. Dr. Lyden’s group has pioneered the study of exosomes and exomeres and how these particles horizontally transfer their cargo to recipient cells, thereby acting as vehicles of intercellular communication in both physiological and pathological conditions. The proposed Center is a natural result of the very complementary expertise of these groups and is well-poised to work collaboratively to advance clinical and basic discoveries in the field of human autoimmunity. .

NIH Research Projects · FY 2025 · 2019-05

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. The successful sequencing of the human genome and the evolution of human health services research in the post-genomic era have offered unprecedented opportunities to transform patient care in digestive diseases. Over the past decade, Weill Cornell Medicine (WCM) has made major investments in biomedical research, as well as research training and infrastructure. This application from WCM that requests support for the research training of six clinical and non-clinical postdoctoral fellows in a renewal application for multidisciplinary research training program (MRTP) in Gastroenterology and Hepatology, with WCM providing funding for an additional training slot. The objective is to recruit outstanding candidates with solid foundations in basic science and train them to apply their knowledge and skills towards addressing important clinically unmet needs in the prevention, diagnosis, and treatment of patients with digestive diseases. MRTP trainees will receive program support for two years during which they will follow a structured and rigorous postdoctoral training program. The MRTP will be a joint effort of 31 eminent preceptors from WCM, Memorial Sloan Kettering Cancer Center (MSKCC) and the Rockefeller University (RU), which constitute a dense network of collaborative researchers, who are international leaders in fields directly relevant to gastroenterology and hepatology. These preceptors have been organized into 3 themed, but interconnected units of research training: gastrointestinal epithelial cell biology, liver diseases, and mucosal immunology and inflammation. These training units will enable the development of content-specific educational programming, as well as increase the efficiency administration within the training program. Oversight will be provided by a Research Training Executive Committee consisting of the Program Director, 3 Associate Program Directors, and 3 additional members who will provide specific guidance on clinical/epidemiologic research within the training program. Three senior preceptors will serve as leaders of the individual training units. We have also assembled an outstanding roster of internal and external advisory board members with a mandate to evaluate the program and provide specific recommendations to improve both its quality and efficiency. The MRTP’s highly personalized training program will include 1) individual development plans; 2) rigorous research training; 3) hands-on experience in cutting-edge methodologies; and 4) an integrated curriculum. Trainees will further benefit from the extensive institutional resources of WCM, MSKCC and RU. Based upon the levels of interest in our fellowship programs, we anticipate a substantial pool of highly qualified clinical and non-clinical candidates for the proposed MRTP. Through its rigorous, structured and highly personalized curriculum, this training program seeks to train future leaders in digestive disease research who are prepared to translate their findings towards improving patient care.

NIH Research Projects · FY 2025 · 2019-04

Major depressive disorder (MDD) is a leading cause of global disability, and approximately 30% of MDD patients are resistant to conventional antidepressant pharmacotherapy. Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) is an FDA-cleared intervention with proven efficacy in treatment-resistant depression, but only 30–40% of these patients achieve remission after a single course. Other studies have shown that rTMS targeting the dorsomedial PFC (DMPFC) is comparably effective, but biomarkers for informing target site selection and predicting differential treatment response are not currently available. Diagnostic heterogeneity has been a major obstacle to biomarker discovery efforts. Recently, we developed and validated an approach to diagnosing four novel MDD subtypes or “biotypes” defined by distinct resting state functional connectivity (RSFC) patterns in Valence System circuits and predicting differing antidepressant responses at the individual level to rTMS targeting the DMPFC. This confirmatory efficacy trial will test a novel, biotype-guided treatment selection strategy motivated by the hypothesis that an individual patient's likelihood of responding to left DLFPC vs. DMPFC rTMS is determined in part by individual differences in 1) the degree to which their symptoms are driven by dysfunction in specific downstream amygdala, striatal, and salience network targets comprising aspects of Valence Systems; and 2) the degree to which dysfunction in those targets can be modulated by stimulating the left DLPFC or DMPFC. Subjects (N=405) will be randomized to receive a) biotype-guided 10 Hz rTMS targeting the DMPFC or left DLPFC; b) to a disconfirmation arm receiving rTMS targeting the opposite site; and c) to a third arm receiving FDA-cleared, standard-of-care 10 HZ rTMS targeting the left DLFPC, regardless of biotype. All patients will be tested before and after treatment on a battery of fMRI, behavioral, and clinical assessments, grounded in RDoC-informed measures of emotion regulation and effort valuation, which will enable us to validate downstream brain circuit treatment targets and test for target engagement, in conjunction with state-of-the-art, anatomically realistic electric field modeling and fiber tractography. The primary goal is to confirm the efficacy of a novel RSFC biomarker-guided approach to differential treatment selection in treatment resistant depression, with the potential for significantly enhanced efficacy compared to the current standard-of-care.

NIH Research Projects · FY 2026 · 2018-12

Project Summary / Abstract Depression is a fundamentally episodic condition, but the mechanisms mediating mood state transitions are not well understood. In our prior work, we investigated how stress and antidepressant effects on synaptic remodeling influence changes in reward-seeking behavior and anhedonia, a core feature of depression. We found that synaptogenesis in prefrontal cortex (PFC) is required for sustaining antidepressant effects on behavior but not for initiating them. Here, we will investigate the molecular, cellular, and circuit-level mechanisms that initiate antidepressant effects on effortful reward-seeking and how they interact with synaptogenesis to generate durable changes in behavior. PFC circuits support reward-seeking behavior by mediating effort valuation computations, which integrate information about the magnitude of an anticipated reward and the expected effort required to obtain it. We have shown how nucleus accumbens (NAc)-projecting PFC cells encode and integrate information about reward- and effort-predictive cues and are critical for reinforcing decisions to expend effort to obtain rewards. We will test a model based on extensive preliminary data in which G protein-coupled receptor (GPCR) signaling in somatostatin (SST) interneurons initiates rapid- acting antidepressant effects on circuit function and behavior. Our efforts will leverage newly developed photopharmacological tools for manipulating GPCR signaling in specific circuit elements with unprecedented spatiotemporal precision, in conjunction with state-of-the-art 2P imaging and optogenetic tools for visualizing and manipulating spine dynamics and circuit function in the living PFC. Our central hypothesis is that Gi/o activation in SST cells initiates antidepressant effects on effortful reward seeking by disinhibiting PFC-NAc cells, restoring coordinated activity in PFC circuits and their capacity to encode reward- and effort-related signals. This, in turn, leads subsequently to the formation of new synapses, which are required for sustaining antidepressant effects over time. Finally, we will test a strategy for identifying SST-enriched Gi/o-coupled GPCRs and validating the most promising candidates as novel therapeutic targets, enabling synergistic effects on effortful reward seeking and anhedonia. Successful completion of our aims will open new avenues for developing synergistic treatment strategies that converge on disinhibition of PFC projection neurons and restoration of lost synapses in specific circuits.

NIH Research Projects · FY 2024 · 2018-09

Project Summary Cancer is a systemic disease. Its growth and malignant progression relies not only on the intrinsic aberrant genetic and epigenetic makeup of tumor cells, but also on the tumor-induced systemic factors which impact cells in local and distant microenvironments. Importantly, there is dynamic crosstalk between the tumor- educated tissues and organs and the tumor itself, especially during metastatic progression. As the tumor reshapes its local microenvironment, coaxing it to support cancer growth, it exerts systemic effects, conquering the immune system and distant organs, leading not only to metastasis but also to vascular changes (vascular leakiness, coagulation), muscular and metabolic changes (cachexia), liver and lung failure, changes in bone density (osteoporosis or osteopetrosis), and neuropathies, but maybe above all, inflammation and immune suppression. The tumor exerts its systemic effects, coaxing the various organ systems of the host to support cancer growth through tumor-secreted factors, such as soluble factors (cytokines and chemokines) and exosomes (and exomeres, the novel particles we recently discovered) nanovesicles that carry complex cargo, including proteins, metabolites, DNA and coding as well as non-coding RNAs. The development of effective anti-metastatic therapies is predicated on our understanding of these iterative and complex interactions between the tumor and its host, and on devising ways to interrupt this communication. We developed novel approaches to analyze the heterogeneity and functional roles of tumor-derived exosomes and exomeres in metastasis as well as their capacity to induce systemic changes. Ultimately, we propose to explore the possibility that inhibition of specific exosome cargo molecules or their targets in hematopoietic cells could reverse immunosuppression, pre-metastatic niche formation and the systemic effects of cancer. In summary, we will focus on studying the mechanisms through which exosomes and exosomes regulate immune system mobilization, metabolic changes and plasticity of pre-metastatic and metastatic niches in cancer models and patients.

NIH Research Projects · FY 2024 · 2018-09

ABSTRACT The principal investigator is a physician scientist who has contributed significant discoveries to the cancer epigenetics field. He has published > 220 scientific papers, 130 of them in the past five years - many of them in high profile journals, and 30 of which were cited by the Faculty of 1000. He has been continuously NCI funded since completing his clinical training in 1997. His proposal will elucidate how B-cell lymphomas arise through disruption of an intricate network of epigenetic mechanisms that regulate and control the humoral immune response. In the generally accepted model for malignant transformation, somatic mutations cause normal cells to manifest aberrant phenotypic hallmarks that define them as malignant tumor cells. However, the PI proposes that malignant transformation occurs in a fundamentally different way in the germinal center (GC) B-cells that give rise to follicular lymphoma (FL) and diffuse large B-cell lymphomas (DLBCL). Specifically, he notes that upon their activation, GC B-cells surprisingly manifest many canonical cancer phenotypes (e.g. massive proliferation, tolerating genomic instability, etc.), which enables them to undergo rapid clonal evolution and immunoglobulin affinity maturation. Strikingly the GC reaction is a transient process after which B-cells extinguish this “pseudo-malignant” phenotype and undergo terminal differentiation, which highlights the PIs critical point that cancer phenotypes are not inherently irreversible. He proposes the novel hypothesis that FLs and DLBCLs arise from a failure of the GC B-cell phenotype to resolve due to disruption in the dynamic equilibrium between histone readers and writers. More specifically, he proposes that the immune synapse between T-follicular helper and GC B-cells normally signals to the epigenome to re-instate the B-cell differentiation program that is epigenetically silenced while B-cells undergo the GC reaction. He hypothesizes that the immune synapse fails to erase GC epigenetic marks and restore B-cell epigenetic marks in the presence of somatic mutations of the histone acetyltransferases CREBBP and EP300, and histone methyltransferases KMT2D and EZH2, which occur early during pathogenesis in ~80% of FL and DLBCL patients suggesting that lymphomas in essence represent uncontrolled GC reactions. Finally he predicts that FLs and DLBCLs with these mutations can be selectively treated using epigenetic-targeted drugs that counteract the effect of these mutations on the epigenome. This latter notion is supported for example by his finding that CREBBP mutant lymphomas are specifically biologically dependent on HDAC3, and that HDAC3 inhibitors reverse the epigenetic, transcriptional and biological effects of CREBBP mutation. For this research he has assembled unique and novel technologies such as GC organoids that allow precise, temporal observation of immune synapse signaling, the necessary genetically engineered mouse models, and extensive libraries of epigenomic profiles in primary human and murine lymphomas. The PI has a track record of translating his findings to the clinic and this proposal will lead to novel rationally designed clinical trials for lymphoma patients.

NIH Research Projects · FY 2025 · 2018-09

PROJECT SUMMARY/ABSTRACT This proposal seeks Dr. Serganova's salary support as a Research Specialist to support Dr. Roberta Zappasodi's research program at Weill Cornell Medicine, Department Hematology and Oncology, to study the role of T-cell responses during immunotherapy in diffuse large B-cell lymphoma (DLBCL). DLBCL is the most common lymphoid neoplasm in adults accounting for ~35% of B-cell non-Hodgkin lymphomas. Despite of relatively good responses to standard treatments, ~40% of patients develop therapy resistance. DLCBLs are genetically heterogeneous and are divided on several subtypes. The MCD-DLBCL subtype is the most clinically aggressive and therapy resistant DLBCL, requiring development of novel therapeutic approaches. One such approach could involve combination with immunotherapy. However, cancer cells evade immune destruction and Dr. Serganova is set to understand the molecular mechanisms of this evasion using her unique experience and expertise in tumor biology, cancer models, and imaging approaches. During previous studies, Dr. Serganova interests were centered on the development of various imaging modalities to understand the complexity of tumor biology in cells and tumors in mice. Recently, in the frame of R50 grant, Dr. Serganova has successfully explored how the modulation of the glycolytic pathway changes the tumor microenvironment and controls the growth of the primary tumors, metastases development, and anti- tumor response during the immunotherapy. Preliminary data acquired during this period show that metabolic deficiencies in tumor cells affect many parameters of the TME, including T cells content and alterations in the vasculature-immune TME compartment with the impact on the tumor vasculature permeability. These studies provide the unique foundation to investigate immunotherapy failures through non-invasive monitoring T cell trafficking, activation and persistence, and understand how interactions between tumor metabolism, microenvironment, targeted antigen expression, and T cell function contribute to evasion of tumor cells from immune destruction. Dr. Serganova is exceptional scientist who has made seminal contributions to the laboratory's research program, including (1) generation of model systems with specific perturbations of metabolic and immune pathways, (2) application of clinically relevant experimental settings in animal studies, and (3) development of advanced imaging technologies. She is continuity, Serganova's immune filling a unique niche within the tha will provide stability, and detailed scientific knowledge to achieve the aims of he NCI-funded grants. Dr. long-time expertise and dedication will advance our understanding of the relationship between system and tumors and will help to develop more effective therapies. Zappasodi laboratory t t

NIH Research Projects · FY 2024 · 2018-08

Project Summary This project aims to re-purpose the safe and well-tolerated gonadotropin-releasing hormone (GnRH) analogue Lupron for use in Alzheimer's Disease (AD). Lupron is currently FDA-approved for prostate cancer, endometriosis and uterine fibroids in adults and for central precocious puberty in children. We propose to confirm and extend results from a prior phase II study (Bowen et al, 2015) that demonstrated that Lupron halted cognitive and functional decline in a subgroup of women with mild-moderate AD who were also taking an acetylcholinesterase inhibitor (AChEI). Our objectives are to replicate, in the same subgroup, Lupron's clinical EFFICACY in this prior trial and to add neuroimaging and plasma BIOMARKERS that will help elucidate Lupron's likely multiple mechanisms of action in AD. These mechanisms include decreasing levels of Luteinizing Hormone (LH) based on extensive preclinical evidence that decreasing LH preserves cognition and decreases amyloid deposition and tau phosphorylation in animal models of AD, as well as new evidence that GnRH analogues may have important anti-inflammatory effects. We will (1) Conduct a three site, double-blind, randomized trial of Lupron (22.5 mg/12 weeks) compared with placebo to evaluate the changes over 48 weeks in cognition and function in women with mild-moderate AD who are also taking a stable dose of AChEI. We hypothesize that patients taking Lupron + AChEI will show a smaller pre- to post-treatment decline in cognition and function when compared to patients taking placebo + AChEI. (2) We will assess Lupron’s effect on structural and functional (ASL-MRI) neuroimaging biomarkers of AD. We hypothesize that patients who receive Lupron + AChEI will demonstrate less atrophy in AD-related brain regions and preserved hippocampal perfusion as compared to those who receive placebo + AChEI. (3) We will assess changes in plasma markers of inflammation. We hypothesize that patients taking Lupron + AChEI, as compared to those taking placebo + AChEI, will show decreased plasma pro-inflammatory cytokines. If this second phase II trial of Lupron + AChEI for AD is positive we will proceed to a phase III trial with the goal of gaining FDA approval for this novel combination therapy for AD. By re-purposing an existing medication, in combination with a current AD treatment, we will be able to build upon extensive previous research and development efforts, reducing the time frame and costs of making this promising therapy available to patients with AD. Results from this project have the potential for significant, near term clinical impact in patients currently suffering from or at risk of AD.

NIH Research Projects · FY 2025 · 2018-08

ABSTRACT: Cardiovascular disease (CVD) is the leading cause of death globally, with 80% of the burden in low- and middle-income countries (LMICs). Yet, the epidemiology of CVD in LMICs is poorly understood given the absence of population-based local data. In 2018, we established the Haiti CVD Cohort (HL143788), the first population-based longitudinal CVD cohort in the region to estimate the prevalence of adjudicated CVD risk factors, diseases, and their association with poverty-related social and environmental determinants. We successfully enrolled 3,005 Haitians and found: environmental (HF), national 1) 30.4% had hypertension (HTN); 2) stress, high salt diet, and lead exposure were associated with increased blood pressure; and 3) 11.6% had heart failure with higher rates among adults <40 years ( This data has informed HTN guidelines and interventions for CVD treatment. 4.5% in Haiti vs 0.3% in the US). With renewal of this R01, we can extend follow- up of this well-characterized cohort to ~22,000 PY to capture critically important incidence data spanning risk factors, events, and poverty-related determinants needed to inform CVD prevention. We will estimate incidence rates across strata and identify high-risk subgroups and population-level modifiable factors that can be targets for future evidence-based CVD prevention. This study is uniquely positioned to address hypotheses specific to CVD in LMICs and among young Black populations, where data in the US is sparse. We hypothesize uncontrolled HTN increases risk for incident HF in young adults, and environmental lead and high dietary salt are major population-level modifiable factors associated with incident CVD. Our Specific Aims are: 1. Determine the 7-year incidence of CVD risk factors and adjudicated events in the Haiti CVD Cohort. CVD risk factors include HTN, diabetes, obesity, hyperlipidemia, kidney disease, poor diet, smoking, physical inactivity, and inflammation. CVD events include HF, stroke, transient ischemic attack, angina, myocardial infarction, and CVD mortality. 2. Identify predictors of incident CVD risk factors and events, including poverty-related social and environmental determinants. We will identify modifiable predictors and high-risk subgroups for future individual-level interventions, with power to detect minimal HRs ≥1.2 across exposures with 10-50% prevalence. We will identify population-level modifiable factors using population attributable risks. 3. Characterize the local context to identify optimal implementation strategies for future evidence- based interventions to prevent CVD at the individual and population level. We will use mixed methods including multisector qualitative interviews and surveys to understand the contextual factors influencing the implementation of future interventions targeting quantitative data in Aims 1-2. This research is essential for fighting the CVD epidemic in LMICs, is enthusiastically supported by the Haitian Ministry of Health, and will inform our understanding of CVD health disparities in the 21st century.

NIH Research Projects · FY 2026 · 2018-08

Project Summary/Abstract Loss of function and viability of rod photoreceptors is central to the etiology of retinitis pigmentosa (RP) which affects 1 in ~4,000. Our lab has a long-term interest in understanding the endosome's role in membrane trafficking of photoreceptors and much has been learned about the outer segment protein targeting. In contrast, we know very little about how the mistrafficked proteins are degraded, and the consequence(s) of the generation of non-degradable wastes. Emerging studies showed the endo-lysosomal system is a genetic hot spot for several neurological diseases such as Alzheimer's and Parkinson's, whose pathology is contributed by both the primary neuronal lesions and sustained microglial inflammation. During the past grant period, we generated a mouse line with rod-specific deletion of VPS35. The early endosomal protein VPS35 is the hub that centrally controls several interconnected trafficking pathways. VPS35 has been genetically linked to Alzheimer's and Parkinson’s. Our results showed that in these mutant mice several outer segment proteins were mislocalized and underwent proteolytic degradation. Strikingly, VPS35 deficient rod terminals accumulated massive lipid-membrane wastes, which were engulfed by the surrounding microglia, which then migrated away to the subretinal space. The latter expressed the molecular signatures of disease-associated microglia identified in Alzheimer's mouse models. The level of sphingolipid, which has been connected to synaptic membrane integrity and neural inflammation, was also abnormally elevated in mutant mice. The overarching goal here is to test a central hypothesis that the engulfment of the rod-derived sphingolipid-rich wastes activates microglia, leading to several functional deficits (e.g., phagocytosis, clearance) and inflammation. We will mechanistically investigate the pathological contribution by sphingolipids (Aim1) and microglia (Aim2) using interdisciplinary and state-of-the-art techniques (e.g., lipidomics, transcriptomes, 3D electron microscopy, multi-antigen flow cytometry) both in vivo and in vitro. We will also address whether inhibiting any of these pathways can offset the sustained microglial inflammation, and in turn, ameliorate retinal pathology. The proposed studies will provide keen insights into the fundamental understanding of the retina homeostasis harnessed by the photoreceptor-microglia crosstalk. They have a high potential to lead to new strategies for treating RP and potentially other neurological diseases with overlapping etiologies.

NIH Research Projects · FY 2026 · 2018-07

Project Abstract In this project, we will identify context-specific enhancers, whose activity is essential for either the growth of primary tumors or for evolution of treatment-resistance in metastatic tumors by modulation of target gene expression. We will identify open chromatin sites in metastatic treatment-resistant breast tumors using whole-genome sequencing of cell-free DNA. Cell-free (cfDNA) enzymatic in plasma predominantly originates from nucleosome-protected parts of DNA after processing. We will develop innovative computational methods that will analyze the nucleosomal signal obtained from whole-genome sequencing of cfDNA from plasma of metastatic cancer patients. We will develop scalable methods to create catalogues of `oncogenic' enhancers that are essential for tumor growth, which may or may not be due to DNA sequence variants at these regions. We will decipher the impact of subtype specific enhancer perturbation on tumor initiation (using CRIPSRa) and continued growth (using CRISPRi) in primary breast cancers. We will test the impact of repressing ~15,000 accessible sites in breast cancer on tumor growth in pooled CRISPR screens in multiple cell lines for each major breast cancer subtype. Importantly, we will also study the impact of activation of the same enhancers on tumor initiation in normal (and malignant) breast cell lines, and we will identify `tumor-suppressive' enhancers that when silenced drive tumor growth. We will also identify oncogenic mutations by integration of 4,427 breast cancer whole-genomes and CRISPR base editing screens. We will focus on specific mutations at cis-regulatory elements, CREs (enhancers, promoters and untranslated regions). For the top 5000 putative noncoding drivers, we will first insert precise mutations via base editing and then, for the top 500 with the most dramatic impact on growth, we will use single-cell sequencing coupled with base editing to decipher their impact on gene expression in cis and in trans. We will also examine the interaction between the top noncoding drivers and aromatase inhibitors, which is a therapy prescribed in many breast cancers.

NIH Research Projects · FY 2026 · 2018-05

PROJECT SUMMARY/ABSTRACT Mammalian cells must move and proliferate to maintain and regenerate tissues and defend themselves against pathogens, but mutations that increase movement or proliferation can also cause cancer. Stem, progenitor, and differentiated cells are often non-motile and quiescent but keep integrating cell-cell contacts, cell-matrix contacts, and receptor inputs, and make two distinct decisions (that are often connected) whether they should start to move and start to proliferate if needed. Several challenges have prevented an understanding of these two decision processes. Genetic approaches in animals cannot readily tackle the co-regulation of large numbers of signaling processes while biochemical analysis of cultured cells often leads to inconclusive results due to the difficulty to synchronize cells and resolve when and where in a cell signaling occurs. Only single cell analysis can resolve the spatial and temporal signaling feedbacks controlling these complex decisions. Our laboratory has developed critically needed fluorescent single-cell activity reporters, rapid perturbation strategies, and automated microscopy and analysis methods to investigate these two fundamental decision processes. To understand the decision to polarize and move, we will use the new tools we developed to explore how external receptor tyrosine kinase signals and cell-cell and cell-matrix contacts synergistically control the initiation and maintenance of gradients in cell signaling and actin organization, and how cells locally direct the signaling gradients and movement. To understand the decision to proliferate, we will investigate the competition mechanism that determines how these same signal inputs at the plasma membrane control the activation of two cyclin-Cdk kinase activities in the nucleus, explore how cells control a proliferation decision process that can still be reversed for many hours before cells commit to proliferate much later, and resolve how this same decision process coordinates the licensing of origins of replication and DNA replication to prevent genome instability and cell death. The outcome of our work will be a quantitative, molecular, and mechanistic understanding of how mammalian cells integrate signals to make decisions to start to move and proliferate, and how mutations that dysregulate these proliferation and migration decisions can cause cancer and other diseases.

NIH Research Projects · FY 2026 · 2018-04

PROJECT SUMMARY AND ABSTRACT: Alzheimer's disease and related dementias (ADRD) are disabling conditions that progressively deprive affected individuals of their cognitive functions, ultimately leading to their inability to perform basic activities of daily living. The brain depends on continuous and well-regulated delivery of energy substrates through the brain blood flow, which is accomplished by elaborate neurovascular control mechanisms that always ensure sufficient cerebral perfusion. One such mechanism, termed functional hyperemia, couples local neural activity with the delivery of blood flow and requires tissue plasminogen activator (tPA) for its full expression, since tPA enables the production of the potent vasodilator nitric oxide during glutamatergic synaptic activity. Neurovascular alterations are observed early in the disease course of ADRD and may promote the expression of cognitive impairment. Amyloid-beta, a significant pathogenic contributor to AD, suppresses functional hyperemia by upregulating the tPA inhibitor PAI-1 resulting in a reduction in tPA activity. However, the cellular sources of PAI-1 remain unclear, and their identification would suggest new approaches to rescue the neurovascular dysfunction induced by amyloid- beta. Perivascular macrophages (PVM), brain resident myeloid cells distinct from microglia located in the perivascular space, can produce large amounts of reactive oxygen species (ROS) which are critical drivers of PAI-1 upregulation. Therefore, we will test the central hypothesis that PVM are the major source of the PAI-1 that leads to tPA deficiency, neurovascular dysfunction, and cognitive deficits induced by amyloid-beta. This hypothesis will be tested in 3 specific aims: (1) PVM are the source of PAI-1 mediating tPA deficiency and neurovascular uncoupling induced by amyloid-beta, (2) PVM CD36 and Nox2, which are responsible for the ROS production in these cells, mediate the PAI-1 upregulation, and (3) PVM PAI-1 contributes to the effects of long-term accumulation of amyloid-beta. These specific aims will be accomplished by employing tour de force approaches, including in vivo and in vitro techniques. The application will widen our knowledge basis for the cellular mechanisms of harmful neurovascular effects of amyloid-beta.

NIH Research Projects · FY 2025 · 2018-02

Abstract The Multidisciplinary Research Training Program (MRTP) in pulmonary disease provides comprehensive research training for individuals committed to a career in lung biology and biomedical research. Our main objective is to provide structured, intensive research and didactic training to pulmonary physicians at the GME fellowship level and Ph.D. scientists with interests in lung disease. Our primary goal is to foster the development of trainee skills needed to pursue successful investigative careers. We recognize the importance of multidisciplinary training and the synergy of interactions among M.D., M.D./Ph.D., D.O. and Ph.D. trainees. We provide broad access to two training modules, basic or clinical science, bridging a translational continuum. For those pursuing a predominantly basic science pathway, the key training activity will be mentored time in a basic research laboratory, supplemented by participation at research conferences and targeted didactic education. For those choosing a more clinical focus, the key training activity will be mentored time conducting a clinically focused research project coupled with didactic training focused on gaining clinical study design skills, while ensuring translational expertise. We appreciate that this basic-translational-clinical continuum is fluid as we focus on providing participants opportunities to explore the translational relevance of their investigative focus. Drs. Fernando Martinez and Augustine Choi serve as co-Program Directors, while Drs. Robert Kaner and Heather Stout-Delgado serve as Associate Program Directors. This group has a long record of investigative and mentoring collaboration, while refining a robust approach to comprehensive assessment of trainee progress with a series of overlapping systems that allow a careful tracking of trainees achieving pre-established benchmarks and timetables. The program leverages a dynamic mentoring team with robust training units comprised of an outstanding multidisciplinary faculty with active research programs in either lung disease or in disciplines relevant to lung disease. Our recipe for success remains a simple and focused one: a) identify three post-doctoral trainees yearly with a demonstrated interest in a research focused career; b) structure a nurturing and productive environment; c) identify a mentor and/or co-mentor ideally suited to provide training and mentoring; and d) provide a period of support (up to 3 years) so that training can progress to a point where the emerging investigator can compete for an entry level award and thrive as an independent investigator.

NIH Research Projects · FY 2025 · 2017-12

Acute kidney disease (AKD) and chronic kidney disease (CKD) are interconnected, pathological syndromes that are quite common in the USA. CKD affects greater than 10% of the world’s population and is an increasing global health burden. The prevalence of CKD in the USA is ~12-14%. Diabetes and hypertension cause ~ two-thirds of CKD cases, while glomerulonephritis, nephrolithiasis, polycystic kidney disease, and toxicants are less common causes. Both AKD and CKD are associated with major cardiovascular complications. Thus, both new treatments for CKD and a deeper understanding of the genesis of CKD are greatly needed. Vitamin A (all-trans retinol, VA), a micronutrient and essential vitamin necessary for life, can only be obtained from our diets. Vitamin A (retinol) is required for kidney development, but much less is known about the functions of this important micronutrient, vitamin A, in the adult kidney. Vitamin A’s metabolites (e.g. retinoic acid (RA)) primarily act by binding to three distinct retinoic acid receptors (RARs) and modifying transcription. In R01 DK113088, a new R01 grant funded in December, 2017, we hypothesized that RARβ played a protective role against CKD and that a RARβ2 selective agonist could inhibit the development of CKD associated with obesity. We have proved these hypotheses and we will build on our exciting results and expand our research into new, but complementary directions. Our hypothesis for Aim (1) is that the RARβ2 selective agonist, AC261066, will be effective in reducing the pathological sequelae after more than one type of kidney injury, not just lipotoxicity-related injury associated with obesity-induced chronic kidney disease. For Aim (2), we hypothesize that vitamin A, via each retinoic acid receptor, including RARγ, which we are just beginning to study, has key actions in multiple, different cell types in the adult kidney and that mice deficient in RARs in specific kidney cells may be models of various human kidney diseases. We propose two specific aims: Specific Aim (1): Because we have evidence that a selective RARβ2 agonist has a therapeutic impact on the development of CKD in one mouse model, we propose to test the efficacy of this RARβ2 agonist in two additional CKD models, potentially creating a rationale to use AC261066 as a lead compound for treatment of CKD and to define its gene targets. Specific Aim (2): Our genetic approach to study the micronutrient vitamin A has been fruitful and has generated several potentially useful models of various types of CKD. Furthermore, our results suggest that the interaction of the kidney with other organ systems varies in different mouse models. Thus, we propose to evaluate the actions of the retinoic acid receptors α, β, and γ in specific cell types in the kidney. We will, through this research, understand the pathologies of CKDs in more depth, elucidate how these pathologies relate to nutrition and aberrant vitamin A signaling, discover new, useful models of CKD, and advance the development of a novel therapeutic for CKD.

NIH Research Projects · FY 2025 · 2017-09

The mission of the Institutional Career Development Core (KL2) is to train, mentor, and develop the next generation of skilled, independent researchers to conduct high-quality clinical and translational research and prepare them to meet the challenges of the current and future complex investigative environment. The KL2 Program has established a track record of providing training for new and emerging technologies (e.g. Nanotechnology, Bioengineering, and Biomedical 3D Printing) in addition to core competency training. Our KL2 graduates have made groundbreaking contributions to the field, and numerous KL2 professional development initiatives have been introduced to inspire innovative research moving forward, include Advanced Certificate in Clinical/Translational (C/T) Investigation and the; a Master’s Program in Clinical and Translational Investigation The Entrepreneurs in Residence Program, where successful entrepreneurs serve as mentors to Scholars and students; the CRESS program, consisting of seminars given by Alumni who discuss their path to success in research and academia, industry, or government; and the Career and Professional Development Workshop. Additionally, the CTSC Health Hackathon was created to cultivate our Scholars’ creativity with a focus on cross-disciplinary teamwork that will stimulate the development of transformative advances in medicine. Great care is taken to ensure that Scholars are matched with highly skilled and trained mentors who are dedicated to nurturing the next generation of healthcare leaders. Mentored Grant writing programs are also provided to help KL2 Scholars and other researchers obtain funded research proposals. Moreover, Scholars can get research support from National Research Support Services and CTSC Research Support Services as needed. With newly expanded initiatives involving creativity, entrepreneurship, team science, precision medicine, informatics, a highly skilled cadre of Scholars will be equipped to tackle the complex biomedical challenges with innovative and impactful solutions to accelerate the clinical and translational continuum. In the proposed funding period, the Program will leverage the strengths of Weill Cornell CTSC, its partners, its resources, and other active collaborators to enable basic and clinical Investigators to achieve successful independence and make significant contributions to the field of Clinical and Translational research. The successful programs will be made available throughout the CTSC network. The planned duration of appointments, is two years, with an optional year if necessary, (e.g. surgeons at 50% time) to three years and their projected number of scholars is (8) and includes early to mid-career, postdoctoral, faculty.