Grant List
Represents Grant table in the DB
GET /v1/grants?page%5Bnumber%5D=1419&sort=program_officials
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=program_officials", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1424&sort=program_officials", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1420&sort=program_officials", "prev": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1418&sort=program_officials" }, "data": [ { "type": "Grant", "id": "15877", "attributes": { "award_id": "1F31DA063126-01", "title": "A statewide examination of the address-level relationships between residential eviction proceedings and overdose events in Rhode Island", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute on Drug Abuse (NIDA)" ], "program_reference_codes": [], "program_officials": [ { "id": 44305, "first_name": "ERIN MARGARET", "last_name": "PARKER", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-09-01", "end_date": "2027-08-31", "award_amount": 49538, "principal_investigator": { "id": 44306, "first_name": "Alexandra", "last_name": "Skinner", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3365, "ror": "", "name": "BROWN UNIVERSITY", "address": "", "city": "", "state": "RI", "zip": "", "country": "United States", "approved": true }, "abstract": "PROPOSAL SUMMARY In the wake of the COVID-19 pandemic, overdose mortality and affordable housing shortages have reached unprecedented levels in Rhode Island and across the United States. Housing insecurity is a known risk factor for overdose, yet the effects of residential eviction—a structural and policy-sensitive cause of housing insecurity—on overdose risks are understudied. Eviction is a complex legal process composed of a series of stages, each of which may impact overdose risk and thus offers opportunity for public health intervention. The objective of this proposal is to pursue a thorough examination of the relationship between residential eviction proceedings (i.e., filing, hearing, and enforcement) and overdose at the address level in Rhode Island, to better inform eviction prevention policies that complement ongoing harm reduction and overdose prevention efforts. The proposed research will leverage the wealth of centralized, high-resolution data available in Rhode Island—and our team’s established relationship with the state health department—to construct a longitudinal dataset with data linked from several administrative sources. We will first characterize the prevalence and time course of eviction proceedings relative to non-fatal or fatal overdose events by conducting sequence and cluster analyses to operationalize variation in the order, duration, and timing of eviction proceedings before and after a given overdose event (AIM 1). We will then estimate the address-level causal effect of residential eviction proceedings on risk of non-fatal and fatal overdose, both overall and by race and ethnicity of overdose decedents, using a sequential target trial approach (AIM 2). The proposed research will be among the first of its kind to link eviction records with address-level health data to characterize heterogeneity in the duration and timing of eviction proceedings, to examine a causal link between eviction and overdose, and to explore differential impacts of eviction on overdose death by race and ethnicity. Because eviction is an intervenable mechanism of housing vulnerability that may be associated with overdose risk, findings from this work may elucidate novel avenues for addressing the intersecting housing and overdose crises in tandem. The proposed research will be completed by the principal investigator with support and mentorship from collaborators with substantial expertise in advanced quantitative methods for life course epidemiology and causal inference. The training activities detailed in this application, focused on advancing skills in epidemiologic study design and longitudinal data analysis and developing a deep contextual knowledge of the social and legal implications of eviction proceedings, will prepare the principal investigator for a career as an independent social epidemiologist and academic researcher.", "keywords": [ "Acute", "Address", "Alaska Native population", "American Indian Population", "Applied Skills", "Black race", "COVID-19 pandemic", "Censuses", "Characteristics", "Cluster Analysis", "Complement", "Complex", "County", "Data", "Data Analyses", "Data Linkages", "Data Set", "Discrimination", "Dose", "Drug user", "Economics", "Epidemiologist", "Epidemiology", "Ethnic Origin", "Event", "Exposure to", "Funding", "Goals", "Harm Reduction", "Health", "Hearing", "Heterogeneity", "Hispanic", "Housing", "Individual", "Intervention", "Knowledge", "Learning", "Legal", "Life Cycle Stages", "Life course epidemiology", "Link", "Mentorship", "Methodology", "Methods", "Neighborhoods", "Overdose", "Patients", "Policies", "Prevalence", "Prevention", "Principal Investigator", "Process", "Race", "Records", "Research", "Research Design", "Research Personnel", "Resolution", "Rhode Island", "Risk", "Risk Factors", "Sequence Analysis", "Series", "Shapes", "Source", "Structural Models", "Time", "Training", "Training Activity", "United States", "United States National Institutes of Health", "Variant", "Work", "career", "data management", "epidemiology study", "health data", "housing insecurity", "legal implication", "longitudinal dataset", "marginalized community", "mortality", "neglect", "novel", "overdose death", "overdose prevention", "overdose risk", "psychosocial", "public health intervention", "residence", "response", "risk prediction", "segregation", "skills", "social", "social implication", "stressor", "structural health determinants" ], "approved": true } }, { "type": "Grant", "id": "15878", "attributes": { "award_id": "1R01AI189484-01", "title": "Role of norovirus capsid dynamics in adaptive immune evasion", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 44307, "first_name": "RODOLFO M", "last_name": "ALARCON", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-09-01", "end_date": "2029-08-31", "award_amount": 2920356, "principal_investigator": { "id": 44308, "first_name": "THOMAS JAMES.", "last_name": "SMITH", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 44309, "first_name": "Christiane", "last_name": "Wobus", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 851, "ror": "", "name": "UNIVERSITY OF TEXAS MED BR GALVESTON", "address": "", "city": "", "state": "TX", "zip": "", "country": "United States", "approved": true }, "abstract": "Human noroviruses are responsible for almost a fifth of all cases of gastroenteritis worldwide. Containment of disease is difficult since as few as ten virions are sufficient to infect a normal adult. Noroviruses evolve continuously with new strains arising every 2-4 years that cause worldwide epidemics. Emergence of new strains can increase the number of cases by 50%. In the US alone, there are more than 2 million outpatient clinic visits, ~100,000 hospitalizations, and ~900 deaths (mostly among adults 65 and older) annually. Globally, there are ~200 million cases among children less than 5 years old, leading to ~50,000 deaths every year. However, no vaccines or antivirals are approved to limit infections. Efforts to develop an effective vaccine have been hindered by a lack of detailed structural information about antibody binding and the mechanisms of antibody escape. Understanding these processes has been difficult with human noroviruses because of the lack of a tissue culture system that supports the generation of a cell culture-derived virus stock and small animal model. To this end, we will be using the highly tractable mouse norovirus system where we have a highly efficient cell culture system, infectious clone, and natural mouse model. We have recently shown, for the first-time, that a virus (i.e., mouse norovirus, MNV) can use host metabolites to switch between two ‘faces’: one recognized by antibodies from recovered animals (apo) and one activated for infection. In conditions found in systemic circulation, the protruding domain (P domain) of the apo form floats above the shell by ~16Å and the loops at the tip are splayed apart. It is this conformation to which the antibody response is made. Once the virus enters the alimentary canal, low pH, bile salts, and metal ions individually and synergistically activate the virus whereby the P domain rotates and contracts onto the shell, and the antibody binding epitope at the tip of the P domain closes. This blocks antibody recognition while enhancing receptor binding. Essentially, each time MNV infects the host, the antibody response is naïve for that conformation. Importantly, we propose that this could explain why the antibody response to norovirus infection in both mice and humans appears to be notoriously short-lived. The goal of this proposal is to test our immune evasion model by creating mutant forms of MNV locked into either the apo or activated states and observing how those changes affect the pathogenesis and immune response in the host. These studies will detail the activation process at the molecular level, elucidate the reason why caliciviruses evolved such mobile P domains, and greatly impact the development of norovirus vaccines and therapeutics. Finally, subsequent to our publications, similar host metabolite immune evasion was observed with COVID-19. Therefore, our results will increase awareness of possible similar features in other virus families and may become paradigms in the future.", "keywords": [ "2019-nCoV", "5 year old", "Acute", "Adult", "Affect", "Affinity", "Ambulatory Care Facilities", "Animal Model", "Animals", "Annual Reports", "Anti-viral Agents", "Antibodies", "Antibody Affinity", "Antibody Response", "Awareness", "Bile Acids", "Binding", "Biology", "Blocking Antibodies", "C-terminal", "COVID-19", "Calicivirus", "Capsid", "Capsid Proteins", "Case Study", "Cell Culture System", "Cell Culture Techniques", "Cessation of life", "Characteristics", "Child", "Circulation", "Clinic Visits", "Containment", "Contracts", "Cryoelectron Microscopy", "Crystallography", "Development", "Dimerization", "Disease", "Distal", "Dose", "Environment", "Epidemic", "Epitopes", "Exhibits", "Face", "Failure", "Family", "Future", "Gastroenteritis", "Gastrointestinal tract structure", "Generations", "Genetic Variation", "Genome", "Goals", "Hospitalization", "Human", "Immune", "Immune Evasion", "Immune response", "Immunity", "Immunologic Memory", "Immunologics", "In Vitro", "Individual", "Infection", "Ingestion", "Innate Immune Response", "Intestines", "Invaded", "Ions", "Libraries", "Ligands", "Lymphatic System", "Mediating", "Metals", "Modeling", "Molecular", "Molecular Conformation", "Mus", "Mutagenesis", "Norovirus", "Pathogenesis", "Pathogenicity", "Persons", "Population", "Process", "Property", "Publications", "Retinal blind spot", "Role", "Rotation", "Series", "Site", "Spleen", "Structure", "Support System", "Surface", "Symptoms", "System", "Tertiary Protein Structure", "Testing", "Therapeutic", "Time", "Tissues", "Vaccines", "Viral Pathogenesis", "Virion", "Virus", "Viviparous-1 protein", "Work", "acute infection", "adaptive immune response", "adaptive immunity", "bile salts", "biophysical techniques", "design", "gastrointestinal epithelium", "human old age (65+)", "improved", "in vivo", "in vivo evaluation", "mouse model", "mutant", "oral infection", "receptor", "receptor binding", "recombinant virus", "reverse genetics", "structural biology", "tissue culture", "tool", "vaccine development", "viral RNA", "volunteer" ], "approved": true } }, { "type": "Grant", "id": "15944", "attributes": { "award_id": "1R01AI195454-01", "title": "Hijacking the neonatal Fc receptor: the novel biology of arterivirus entry, transmission, and persistence", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 44307, "first_name": "RODOLFO M", "last_name": "ALARCON", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2026-04-03", "end_date": "2031-03-31", "award_amount": 615446, "principal_investigator": { "id": 31459, "first_name": "Adam Lee", "last_name": "Bailey", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3403, "ror": "", "name": "UNIVERSITY OF WISCONSIN-MADISON", "address": "", "city": "", "state": "WI", "zip": "", "country": "United States", "approved": true }, "abstract": "Understanding novel mechanisms by which animal viruses enter cells, evade immunity, and cause disease has scientific and public health importance. Arteriviruses are an understudied family of RNA viruses (related to coronaviruses) that infect a wide variety of mammals. The host and viral factors that determine arterivirus disease, persistence, and cross-species transmission remain unknown and unpredictable. This lack of understanding has implications for predicting/thwarting arterivirus emergence in humans, as some arteriviruses have been shown to infect human cells. Macrophages are exclusively infected by most arteriviruses, but the subpopulation(s) of macrophages that support arterivirus replication remain poorly defined. The process by which arteriviruses enter cells is highly novel and also poorly understood. Each virion displays an unusually large set of surface glycoproteins (7-11 depending on the virus) that are unlike any known viral fusion machinery. The macrophage-specific molecule CD163 is a required arterivirus receptor, yet CD163 by itself is insufficient to mediate arterivirus entry. We recently identified the neonatal Fc receptor (FcRn) as an important entry factor that arteriviruses use together with CD163 to gain entry into cells. Aim 1 of this project builds upon this discovery to define the molecular details of the arterivirus:FcRn interaction. In Aim 1a, we will map the site(s) on FcRn that are critical for arterivirus engagement by creating chimeric FcRn molecules that incorporate features of arterivirus-permissive and -resistant FcRn orthologs, with the goal of defining the domains, motifs, and residues involved in arterivirus/FcRn interactions. In Aim 1b, we will generate chimeric arteriviruses that contain combinations of glycoproteins from different arteriviruses, seeking to define the viral glycoproteins, domains, motifs, and residues involved in FcRn engagement. In Aim 1c, we will continue to develop our understanding of the host factors required for arterivirus entry by performing screens to identify additional host factors that are functionally redundant with FcRn for the viral entry process. In Aim 2, we will use the murine arterivirus (lactate dehydrogenase-elevating virus, LDV), which causes life-long viremia in adult mice, to understand several aspects of arterivirus infection in vivo. In Aim 2a, we will use a nanoluciferase-expressing LDV to perform body-wide imaging and identify the tissues that support LDV infection over time. In Aim 2b, we will hone in key tissues and identify the macrophage populations within these tissues that support LDV infection and determine how persistent arterivirus infection impacts recovery of target cell populations. Finally, in Aim 2c we will use FcRn-knockout mice to determine whether arteriviruses hijack FcRn’s physiologic role in placental biology, potentially explaining the high efficiency with which arteriviruses transmit vertically. This project will provide insights into novel mechanisms of viral entry, macrophage infection and dysfunction, viral persistence, and vertical transmission through the study of the neglected “pre-emergent” family of mammalian viruses, the arteriviruses.", "keywords": [ "Acute", "Acute Disease", "Adult", "Anatomy", "Animals", "Arterivirus", "Arterivirus Infections", "Biology", "Cell Culture Techniques", "Cell Line", "Cell Surface Receptors", "Cells", "Clustered Regularly Interspaced Short Palindromic Repeats", "Complex", "Coronavirus", "Development", "Disease", "Distant", "Family", "Family suidae", "Farm", "Fc Receptor", "Fetus", "Functional disorder", "Glycoproteins", "Goals", "Human", "Image", "Immune system", "Immunity", "Immunoglobulin G", "Industry", "Infection", "Integration Host Factors", "Knock-out", "Knockout Mice", "Knowledge", "Laboratories", "Lactate dehydrogenase-elevating virus", "Life Cycle Stages", "Link", "Macrophage", "Mammals", "Maps", "Mediating", "Membrane Glycoproteins", "Modeling", "Molecular", "Mus", "Orthologous Gene", "Phase", "Physiological", "Placenta", "Placental Biology", "Pneumonia", "Population", "Positioning Attribute", "Predisposition", "Primates", "Process", "Public Health", "RNA Viruses", "Recovery", "Reporter", "Research", "Resistance", "Retinal blind spot", "Role", "Site", "Structure", "Surface", "Syncytiotrophoblast", "System", "Time", "Tissues", "Tropism", "Vertical Transmission", "Viral", "Viral Hemorrhagic Fevers", "Viremia", "Virion", "Virus", "Virus Receptors", "Virus Replication", "Whole Organism", "cell immortalization", "chronic infection", "cross-species transmission", "economic impact", "fetal", "genome-wide", "in utero", "in vivo", "insight", "medical countermeasure", "model organism", "nanoluciferase", "neglect", "neonatal Fc receptor", "novel", "permissiveness", "pregnant", "receptor", "reverse genetics", "time use", "transmission process" ], "approved": true } }, { "type": "Grant", "id": "15879", "attributes": { "award_id": "1R01HD120113-01", "title": "DISSECTING MECHANISMS OF INFLAMMATORY SIGNALING ACROSS THE MATERNAL FETAL INTERFACE", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)" ], "program_reference_codes": [], "program_officials": [ { "id": 44310, "first_name": "DENISE", "last_name": "RUSSO", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-09-15", "end_date": "2028-05-31", "award_amount": 2255352, "principal_investigator": { "id": 44311, "first_name": "Christiana Elizabeth", "last_name": "Smith-Anderson", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3385, "ror": "", "name": "UNIVERSITY OF COLORADO DENVER", "address": "", "city": "", "state": "CO", "zip": "", "country": "United States", "approved": true }, "abstract": "Infants exposed in utero to maternal inflammatory disorders are at risk of long-lasting health impacts, such as altered neurodevelopmental outcomes or dysregulated immune responses. When maternal infections are the inflammatory stimulus, these adverse neonatal outcomes can occur in the absence of congenital infection. Our preliminary data show that infants who are HIV-exposed, but uninfected experience high rates of morbidity and mortality that are associated with maternal inflammation in a dose-dependent fashion. Early reports suggest that acute maternal infection with COVID-19 can have profound impacts on fetal immune development. Inflammatory signaling across the maternal-fetal interface during a critical fetal developmental window is likely to be responsible for these adverse neonatal outcomes. However, critical gaps exist in our understanding of how inflammatory signals are transferred across the placenta. The overarching goal of this proposal is to determine the cellular and molecular mechanisms involved in the transfer of inflammatory signals across the maternal-fetal interface in the setting of acute or chronic viral infection. We will capitalize upon access to samples from pregnancies complicated by either HIV, which results in chronic inflammation, or SARS-CoV-2, which causes severe acute inflammation, to address the following Specific Aims: 1) to profile the transcriptomic signatures of heterogenous maternal and fetal cell types in their in situ environment within placentas from pregnancies affected by HIV or SARS-CoV-2 versus healthy pregnancies; 2) to compare concentrations of inflammatory and regulatory biomarkers in maternal and infant peripheral blood, cord blood and placentas from term pregnancies affected by HIV or SARS-CoV-2 versus healthy pregnancies and determine their association with placental gene expression; and 3) to characterize inflammatory signaling across the maternal-fetal interface using a 3- dimensional in vitro model that incorporates key placental cell types. This proposal includes several innovative components, including the use of advanced bioinformatics to directly correlate placental gene expression data from a single-cell spatial transcriptomics assay to the peripheral concentrations of inflammatory biomarkers within the same participants, and the development of a novel Transwell-based model of the human placenta that can be used to mechanistically interrogate the role of each cell type in the transfer or inflammatory signals. Disentangling the mechanisms responsible for the transfer of inflammation across the maternal-fetal interface will ultimately allow for the identification of therapeutic agents to modulate inflammation in pregnancy, thereby preventing adverse neurodevelopmental and/or immunologic consequences to the fetus.", "keywords": [ "2019-nCoV", "3-Dimensional", "Acute", "Address", "Affect", "Amniotic Fluid", "Animals", "Architecture", "Bioinformatics", "Biological Assay", "Biological Markers", "COVID-19", "COVID-19 diagnosis", "Cells", "Chronic", "Circulation", "Coculture Techniques", "Data", "Decidua", "Decidual Cell Reactions", "Development", "Disease", "Dose", "Endometrial Stromal Cell", "Endothelial Cells", "Environment", "Equilibrium", "Exposure to", "Fetal Growth Retardation", "Fetal Tissues", "Fetus", "Fibroblasts", "Future", "Gene Expression", "Geography", "Goals", "HIV", "HIV-exposed uninfected infant", "HIV/HBV", "Health", "Human", "Hypertension", "Immune", "Immune response", "Immunologics", "Impairment", "In Situ", "Infant", "Infant Health", "Infection", "Inflammation", "Inflammatory", "Innate Immune Response", "Insulin-Dependent Diabetes Mellitus", "Interleukin-1 alpha", "Interleukin-6", "Leukocytes", "Macrophage", "Malaria", "Maternal-Fetal Exchange", "Measures", "Mediator", "Mesenchymal Stem Cells", "Modeling", "Molecular", "Morbidity - disease rate", "Mothers", "Neonatal", "Obesity", "Outcome", "Participant", "Pathway interactions", "Peripheral", "Placenta", "Plasma", "Pregnancy", "Pregnancy Complications", "Pregnant Women", "Premature Labor", "Proteomics", "Reporting", "Respiratory Tract Infections", "Risk", "Role", "Sampling", "Second Pregnancy Trimester", "Signal Transduction", "Source", "Spontaneous abortion", "Stimulus", "TNF gene", "Testing", "Therapeutic Agents", "Tissues", "Umbilical Cord Blood", "Umbilical vein", "Villous", "Virus Diseases", "adverse pregnancy outcome", "cell type", "chemokine", "congenital infection", "cytokine", "differential expression", "ex vivo perfusion", "experience", "fetal", "fetus cell", "healthy pregnancy", "human-based research", "immunoregulation", "in vitro Model", "in vivo", "inflammatory milieu", "innovation", "maternal inflammation", "mortality", "neonatal outcome", "novel", "offspring", "peripheral blood", "pregnant", "prenatal exposure", "prevent", "spatial transcriptomics", "transcriptomics", "trophoblast" ], "approved": true } }, { "type": "Grant", "id": "15882", "attributes": { "award_id": "1K99AI194972-01", "title": "The Role of Tunneling Nanotubes and Mitochondrial programming in HIV-Associated Placental Dysfunction", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Allergy and Infectious Diseases (NIAID)" ], "program_reference_codes": [], "program_officials": [ { "id": 44315, "first_name": "UDAY K", "last_name": "SHANKAR", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-09-01", "end_date": "2027-08-31", "award_amount": 156744, "principal_investigator": { "id": 44316, "first_name": "Rafael", "last_name": "Tomoya Michita", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2610, "ror": "", "name": "BAYLOR COLLEGE OF MEDICINE", "address": "", "city": "", "state": "TX", "zip": "", "country": "United States", "approved": true }, "abstract": "/ ABSTRACT HIV is known to be transmissible from mother to the developing fetus during pregnancy, leading to adverse health outcomes for both. Although HIV is linked to placental pathologies, there is still a large gap in knowledge about the mechanisms underlying HIV-associated pregnancy complications, despite four decades of research in general on HIV topics. The objective of this project is to investigate the role of intercellular conduits composed of F-actin microtubules that connect plasma membranes of neighboring cells enabling cytoplasmic continuing and intercellular transfer of cargo. These conduits are known as tunneling nanotubes (TNTs). Recent investigations by the PI and others have demonstrated that other viruses such as Zika and SARS-CoV-2 induce the formation of TNTs in placental trophoblast cells, and there is evidence they serve as a means of mitochondrial transfer and possibly viral transfer that promotes infectious spread. There is evidence that HIV induces TNT formation in neurons, but it is not known whether the virus has this effect on placental cells. Building on prior studies and ongoing work by the PI, the central hypothesis of this project is that HIV uses TNTs to spread infection in trophoblasts, and that TNTs mediate placental dysfunction by transferring damaged mitochondria and adversely reprogramming trophoblast metabolism. This metabolic reprogramming may contribute to placental dysfunction and adverse pregnancy outcomes. Aim 1 of this project will elucidate the molecular mechanisms of TNT formation between HIV-infected immune cells and trophoblasts. Aim 2 will determine the impact of HIV on mitochondrial dynamics and transfer and resulting trophoblast function. These two aims will be pursued during the final postdoctoral training period of the K99 phase. Aim 3 seeks to identify how HIV-exposed mitochondria reprogram trophoblast biology, impairing placental function and affecting fetal development in vivo. This third aim will be pursued during the R00 phase of the project. Successful completion of these aims will provide new insights into the mechanisms underlying HIV infection, identifying potential therapeutic targets to mitigate vertical transmission and placental pathologies caused by HIV and other viruses. During the mentored phase, the PI will gain expertise in primary cell culture, metabolomics, trophoblast organoids, and mitochondrial epigenetics to examine how HIV infects the placenta and disrupts cellular metabolism—establishing a foundation for the R00 phase. With guidance from the advisory team, this training and research will contribute to the identification of therapeutic strategies to improve outcomes for infants and individuals with HIV, while positioning the investigator to establish an independent, competitive R01-funded laboratory at the intersection of HIV, TNTs, placental biology, and mitochondria.", "keywords": [ "2019-nCoV", "Actins", "Advisory Committees", "Affect", "Affinity Chromatography", "Anti-viral Response", "Automobile Driving", "Biology", "Bypass", "Cell Physiology", "Cell Separation", "Cell Survival", "Cell fusion", "Cell membrane", "Cells", "Chronic", "Cloning", "Coculture Techniques", "Confocal Microscopy", "Coupled", "Cytoplasm", "Cytoskeleton", "DNA", "Data", "Deoxyadenosines", "Development", "Disproportionately impacts women", "Epigenetic Process", "F-Actin", "Fetal Development", "Fetus", "Flow Cytometry", "Foundations", "Functional disorder", "Funding", "Genes", "Genetic Transcription", "HIV", "HIV Infections", "HIV-1", "Health", "Image Cytometry", "Immune", "Immune Evasion", "Immune response", "Immunoprecipitation", "Impairment", "In Vitro", "Individual", "Infection", "Inflammation", "Investigation", "Knowledge", "Label", "Laboratories", "Link", "Mass Spectrum Analysis", "Measures", "Mediating", "Mentors", "Metabolic", "Metabolic Pathway", "Metabolic dysfunction", "Metabolism", "Microtubules", "Mitochondria", "Mitochondrial DNA", "Modeling", "Modification", "Molecular", "Mothers", "Mus", "Mutation", "Neurons", "Organoids", "Outcome", "Oxidative Phosphorylation", "Pathology", "Pathway interactions", "Patients", "Perinatal Infection", "Phase", "Placenta", "Placental Biology", "Positioning Attribute", "Pregnancy", "Pregnancy Complications", "Pregnant Women", "Primary Cell Cultures", "Process", "Proteins", "Quantitative Reverse Transcriptase PCR", "Reactive Oxygen Species", "Recombinants", "Regulation", "Research", "Research Personnel", "Risk", "Role", "Site-Directed Mutagenesis", "Study models", "System", "T-Lymphocyte", "Techniques", "Tertiary Protein Structure", "Testing", "Therapeutic", "Training", "Validation", "Vertical Transmission", "Viral", "Virion", "Virus", "Virus Diseases", "Visualization", "Western Blotting", "Work", "ZIKA", "Zika Virus", "adverse pregnancy outcome", "antiretroviral therapy", "experimental study", "fetal", "global health", "heteroplasmy", "improved outcome", "in vivo", "infant outcome", "insight", "knock-down", "live cell imaging", "metabolomics", "mitochondrial dysfunction", "mouse model", "mutant", "placental trophoblasts", "post-doctoral training", "pregnant", "programs", "protein protein interaction", "reproductive age", "single molecule real time sequencing", "single-cell RNA sequencing", "stem cells", "therapeutic target", "transmission process", "tropho" ], "approved": true } }, { "type": "Grant", "id": "15885", "attributes": { "award_id": "1U48DP006966-01", "title": "BREATHE WELL: Development and Implementation of a Training Program to Increase Vaccination in Early Childcare and Education Centers", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Center for Immunization and Respiratory Diseases (NCIRD)" ], "program_reference_codes": [], "program_officials": [ { "id": 44318, "first_name": "NATALIE", "last_name": "DARLING", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-09-30", "end_date": "2029-09-29", "award_amount": 499950, "principal_investigator": { "id": 44319, "first_name": "Roshanak", "last_name": "Mehdipanah", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 25237, "first_name": "Marc A", "last_name": "Zimmerman", "orcid": null, "emails": "[email protected]", "private_emails": null, "keywords": "[]", "approved": true, "websites": "[]", "desired_collaboration": "", "comments": "", "affiliations": [ { "id": 770, "ror": "", "name": "UNIVERSITY OF MICHIGAN AT ANN ARBOR", "address": "", "city": "", "state": "MI", "zip": "", "country": "United States", "approved": true } ] }, { "id": 44320, "first_name": "Abram Luther", "last_name": "Wagner", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 770, "ror": "", "name": "UNIVERSITY OF MICHIGAN AT ANN ARBOR", "address": "", "city": "", "state": "MI", "zip": "", "country": "United States", "approved": true }, "abstract": "/ ABSTRACT Early childcare and education (ECE) centers are trusted institutions that engage with parents regularly, positioning them as key messengers for childhood immunization and respiratory health promotion. While ECE centers ensure compliance with mandated vaccines, their potential to support uptake of non-mandated immunizations—such as influenza vaccine, COVID-19 vaccine, maternal RSV vaccine, and nirsevimab antibody—remains underutilized. The BREATHE Well (Building Readiness, Engagement, and Trust for Healthy Environments) Toolkit is an evidence-based intervention designed to enhance ECE-originating vaccine communication, training ECE staff to effectively engage parents on immunization topics. This study will evaluate the feasibility, acceptability, and effectiveness of the BREATHE Well toolkit using a cluster- randomized controlled trial (RCT). The project will be guided by three specific aims: (1) Develop and refine the BREATHE Well toolkit through formative research, incorporating input from ECE staff, parents, and public health officials; (2) Assess the acceptability and feasibility of the toolkit through focus groups and surveys with ECE staff and parents in demonstration sites within Michigan; and (3) Evaluate the effectiveness of the toolkit in a cluster-randomized trial of ECE centers, measuring changes in parental vaccine confidence, intent to vaccinate, and staff capacity to serve as trusted messengers. The BREATHE Well toolkit will be designed as a scalable approach usable in different types of ECEs. Findings from this study will inform best practices for integrating vaccine-related education into ECE settings, with the goal of increasing parental vaccine confidence and improving uptake of recommended immunizations.", "keywords": [], "approved": true } }, { "type": "Grant", "id": "15886", "attributes": { "award_id": "1R01DA061028-01A1", "title": "Thyroid hormone mediated reprogramming of the basolateral amygdala by adolescent social deprivation", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute on Drug Abuse (NIDA)" ], "program_reference_codes": [], "program_officials": [ { "id": 44321, "first_name": "DA-YU", "last_name": "WU", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-09-30", "end_date": "2030-05-31", "award_amount": 623650, "principal_investigator": { "id": 44322, "first_name": "Deena M.", "last_name": "Walker", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2648, "ror": "", "name": "OREGON HEALTH & SCIENCE UNIVERSITY", "address": "", "city": "", "state": "OR", "zip": "", "country": "United States", "approved": true }, "abstract": "Social disconnection in humans, particularly during adolescence, is associated with substance use disorder vulnerability. In mice, adolescent social isolation profoundly alters reward processing in adulthood; increasing the preference for drugs of abuse, enhancing associative learning, altering dopaminergic signaling and transcription within the BLA and extended reward circuitry. Intriguingly, these phenomena are all also associated with thyroid hormone signaling. Further, dysregulation of thyroid hormone in early life is associated lifetime risk for reward-related mood disorders and altered development of monoaminergic systems. In adults, thyroid hormone dysregulation is associated with substance- and alcohol use disorders. Therefore, we propose that the persistent impacts of adolescent social isolation result from transient dysregulation of thyroid hormone signaling during the sensitive period of adolescence. Thyroid hormones, when bound to their receptors, are transcription factors that mediate various epigenetic processes and regulate gene expression. Aberrant thyroid hormone signaling at critical developmental periods persistently alters transcription in other tissues through epigenetic reprogramming of thyroid hormone sensitive genes. Despite its critical role in neurodevelopment and its link to substance use disorder, the consequences of thyroid hormone dysregulation in adolescence, a key period for reward circuitry development and substance use disorder vulnerability, is virtually unknown. Our preliminary data suggest that circulating thyroid hormones and expression of its receptors are transiently disrupted in adolescence by social isolation and this is associated with enhanced expression of GABAergic neuronal markers in the adult basolateral amygdala (BLA), a key reward-related brain region Here, we will test the hypothesis that thyroid hormone is critical for development of the basolateral amygdala (BLA) during adolescence and that isolation-induced disruptions to the thyroid hormone system result in lasting epigenetic reprogramming of the reward circuitry to increase cocaine sensitivity. First, we will determine how adolescent social isolation impacts thyroid hormone-mediated transcription in the BLA (Aim 1). Then we will determine if thyroid hormone dysregulation induced by adolescent isolation disrupts cell-type specific transcriptional profiles within the BLA (Aim 2). Finally, we will disrupt thyroid hormone receptor beta levels specifically during adolescence to determine its role in reward-related behavior in (Aim 3). Together, these foundational studies will establish a role for thyroid hormone-mediated programming of the BLA and uncover novel mechanisms of isolation-induced reprogramming of SUD vulnerability during adolescence - an endpoint that has become even more urgent given the known reductions in social interactions due to the mitigation of Covid-19 for the current generation of adolescents.", "keywords": [ "Acute", "Address", "Adolescence", "Adolescent", "Adult", "Agonist", "Amygdaloid structure", "Animals", "Association Learning", "Behavior", "Behavioral", "Binding", "Brain", "Brain region", "COVID-19", "Cell Nucleus", "Cells", "Cleavage Under Targets and Release Using Nuclease", "Cocaine", "Data", "Development", "Environment", "Epigenetic Process", "Exhibits", "Gene Expression", "Gene Expression Profile", "Generations", "Genes", "Genetic Transcription", "Goals", "House mice", "Human", "Individual", "Intervention", "Life", "Link", "Loneliness", "Measures", "Mediating", "Messenger RNA", "Mood Disorders", "Mus", "Neurons", "Peripheral", "Phenocopy", "Positioning Attribute", "Predisposition", "Procedures", "RNA", "Rewards", "Risk Factors", "Role", "Self Administration", "Signal Transduction", "Social Interaction", "Social isolation", "Substance Use Disorder", "System", "Testing", "Thyroid Hormone Receptor", "Thyroid Hormone Receptor β", "Thyroid Hormones", "Time", "Tissues", "Triiodothyronine", "Upregulation", "Work", "addiction", "adolescent brain development", "alcohol use disorder", "cell type", "critical developmental period", "drug of abuse", "drug reward", "experience", "experimental study", "hormonal signals", "knock-down", "later life", "lifetime risk", "mature animal", "molecular phenotype", "neurodevelopment", "new therapeutic target", "novel", "overexpression", "peer", "pre-clinical", "preference", "programs", "receptor", "response", "reward circuitry", "reward processing", "social", "social deprivation", "substance use", "thyroid disruption", "transcription factor", "transcriptional reprogramming", "transcriptome sequencing", "virtual" ], "approved": true } }, { "type": "Grant", "id": "15897", "attributes": { "award_id": "7R01DA059176-02", "title": "Multimodal Analysis of Gestational Health and Placental Injury in Opioid-Affected Pregnancies", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute on Drug Abuse (NIDA)" ], "program_reference_codes": [], "program_officials": [ { "id": 44321, "first_name": "DA-YU", "last_name": "WU", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-15", "end_date": "2026-07-31", "award_amount": 1247483, "principal_investigator": { "id": 22880, "first_name": "Elizabeth E", "last_name": "Krans", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 848, "ror": "", "name": "UNIVERSITY OF PITTSBURGH AT PITTSBURGH", "address": "", "city": "", "state": "PA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [ { "id": 28076, "first_name": "Yingshi", "last_name": "Ouyang", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, { "id": 28077, "first_name": "Yoel", "last_name": "Sadovsky", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 1167, "ror": "", "name": "CHILDREN'S RESEARCH INSTITUTE", "address": "", "city": "", "state": "DC", "zip": "", "country": "United States", "approved": true }, "abstract": "Opioids are medically used for safe pain relief and management. However, illicit opioid use has substantially increased across the US in the past decade, with further worsening during the COVID-19 pandemic, leading to a profound impact on human health. Specifically, opioid use disorder (OUD) during pregnancy poses an increased risk of pregnancy-associated maternal morbidity and mortality, fetal growth restriction (FGR) and related complications, neonatal opioid withdrawal syndrome, and long-term neurobehavioral effects. Some of these risks persist despite the use of safer opioids, such as buprenorphine and methadone, medications for OUD (MOUD) patients. Whereas current studies center mainly on transplacental opioid transport to the fetus and the adverse effects of opioids on infants, the direct impact of illicit and prescription opioids on placental development, differentiation, and function are largely unexplored. The placental floating villi mediate maternal- fetal gas exchange, nutrient uptake, waste release immune defense and the production of hormones and extracellular vesicles (EVs). These villi are covered by a layer of multinucleated, terminally differentiated syncytiotrophoblasts (STBs), which forms the feto-placental frontline that is directly exposed to opioids in the maternal blood. Subjacent to this layer are mononucleated, progenitor cytotrophoblasts (CTBs), which replenish the STB layer through the process of differentiation and fusion. Importantly, injuries to the STB and CTB layers are implicated in pregnancy-associated complications, including FGR and stillbirth. Here we seek to investigate opioid-dependent placental injury, focusing on the most critical and unique layer of placental trophoblasts. We will enroll participants with OUD, including illicit opioids and MOUD (buprenorphine, methadone), examine their pregnancy course and their children’s health through the first year postpartum. Using biospecimens from each participant, including maternal plasma and urine across the three trimesters, placental biopsies and fetal cord blood at delivery, we will employ multimodal cutting-edge technologies, including single-cell RNAseq, spatial transcriptomics, protein chip cytometry and placenta EV RNA profiling, and explore the molecular and cellular processes affected by opioids in the maternal-placental-fetal trio- ecosystem. To gain mechanistic insights into the functional changes in gene expression and EV cargo, we will use an array of model systems, including human trophoblast stem cells and cultured primary human trophoblasts, and mechanistically interrogate pathways underlying opioid injury. We will further correlate key molecular signatures with clinical assessment, including maternal gestational disorders, perinatal and infant neurodevelopmental outcomes. Together, our strategic plan, bolstered by our transdisciplinary team, enables us to address critically important knowledge gaps related to human placenta biology in opioid-affected pregnancies.", "keywords": [], "approved": true } }, { "type": "Grant", "id": "15890", "attributes": { "award_id": "1R43HL176305-01A1", "title": "Development of a tissue-targeted non-thrombotic EPO derivative", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Heart Lung and Blood Institute (NHLBI)" ], "program_reference_codes": [], "program_officials": [ { "id": 44326, "first_name": "NITIN", "last_name": "AGRAWAL", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-09-20", "end_date": "2026-08-31", "award_amount": 306658, "principal_investigator": { "id": 44327, "first_name": "Robert Rogers", "last_name": "Yocum", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 3394, "ror": "", "name": "GENERAL BIOLOGICS, INC.", "address": "", "city": "", "state": "MA", "zip": "", "country": "United States", "approved": true }, "abstract": "“Development of a tissue-targeted non-thrombotic EPO derivative.” Chronic obstructive pulmonary disease (COPD) affects 16 million people in the US and is the third leading cause of death in the world, with an estimated 500 million cases worldwide. In the US the primary cause is cigarette smoking, but in most of the world the cause is air pollution. In this disease, the airways (bronchioles) are constricted and the alveoli are distended and never fully contract. Current treatments use drug inhalers that open up the airways, but these treatments are only partially effective. In addition, about 2 million of the US COPD patients are also anemic, so that oxygen delivery is particularly poor. Erythropoietin (EPO) is a hormone that mediates the body’s response to massive blood loss (hemorrhage). EPO is used to treat anemia in kidney failure, cancer, etc., based on its stimulation of red blood cell production. EPO also has a useful tissue-protective activity that can reduce effects of oxygen limitation that damage the heart, brain, and other tissues. However, EPO also enhances blood clotting and increases frequency of heart attacks, strokes and deep vein thrombosis when given to anemic patients. To address COPD and other problems of oxygen delivery, General Biologics is developing an engineered protein, termed “EPO-H” (EPO for Hypoxia), that retains the red blood cell producing and tissue-protective activities of EPO, but lacks the blood clotting side effects. EPO-H will also have a long plasma half-life, to allow for infrequent dosing, patient convenience, and reduced burden on the health care system. The net effect should be that, compared to current commercial versions of EPO, our protein (“EPO-H”) will maintain production of red blood cells, show increase neuroprotection, and have significantly reduced or eliminated blood-clotting site effects. Natural EPO is not currently given to COPD patients or patients with disorders such as cystic fibrosis or extreme Covid-19 requiring hospitalization and mechanical ventilation. Our experimental aims are: (1) General Biologics will produce engineered protein for all of the experiments and will test the proteins for blood-based surrogate markers of hypoxia resistance and blood-clotting, to establish a dose at which the therapeutic effect is expected but side effects are not.; (2) University of Maryland will demonstrate that EPO-H can promote survival of mice in a low- oxygen environment; and also (3) demonstrate that EPO-H does not enhance clot size in a mouse model of deep vein thrombosis, even though natural EPO does increase the size of blood clots in mice with deep vein thrombosis.", "keywords": [ "Address", "Affect", "Air Pollution", "Alveolus", "Anemia", "Antibodies", "Atmosphere", "Binding", "Biological Assay", "Biological Products", "Blood - brain barrier anatomy", "Blood Platelets", "Blood Proteins", "Blood coagulation", "Blood flow", "Blood specimen", "Brain", "Bronchioles", "C57BL/6 Mouse", "COVID-19", "COVID-19 patient", "Cause of Death", "Cell Survival", "Cells", "Chimeric Proteins", "Chronic Obstructive Pulmonary Disease", "Coagulation Process", "Collaborations", "Contracts", "Core Facility", "Cystic Fibrosis", "Deep Vein Thrombosis", "Development", "Disease", "Dose", "Dose Limiting", "Drug Kinetics", "Drug usage", "Elements", "Environment", "Epoetin Alfa", "Erythrocytes", "Erythropoietin", "Erythropoietin Receptor", "Flow Cytometry", "Frequencies", "Glycophorin", "Goals", "Half-Life", "Health Care Systems", "Hematopoiesis", "Hematopoietic stem cells", "Hemorrhage", "Hormones", "Hospitalization", "Hypoxia", "Inferior vena cava structure", "Inhalators", "Kidney Failure", "Lead", "Malignant Neoplasms", "Maryland", "Measures", "Mechanical ventilation", "Mediating", "Medical", "Modeling", "Mus", "Mutate", "Mutation", "Myocardial Infarction", "Needles", "Oxygen", "Patients", "Persons", "Pharmaceutical Preparations", "Plasma", "Production", "Protein Engineering", "Proteins", "Reagent", "Research", "Resistance", "Reticulocyte count", "Reticulocytes", "Signal Transduction", "Site", "Stroke", "Surrogate Markers", "Testing", "Therapeutic", "Therapeutic Effect", "Thrombus", "Time", "Tissues", "Universities", "Ventilator", "analytical tool", "cigarette smoking", "constriction", "deprivation", "drug testing", "experimental study", "heart damage", "humanized antibody", "improved", "in vivo", "loss of function", "medical schools", "mouse model", "nanobodies", "neuroprotection", "novel", "preclinical development", "professor", "promote resilience", "resilience", "response", "side effect", "success", "thrombotic" ], "approved": true } }, { "type": "Grant", "id": "15892", "attributes": { "award_id": "7R35GM124918-08", "title": "How the endocytic network mediates specificity of cell signaling", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of General Medical Sciences (NIGMS)" ], "program_reference_codes": [], "program_officials": [ { "id": 44328, "first_name": "KALYNDA K", "last_name": "STOKES", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-09-01", "end_date": "2028-08-31", "award_amount": 419850, "principal_investigator": { "id": 44329, "first_name": "Yan", "last_name": "Yu", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 827, "ror": "", "name": "WASHINGTON UNIVERSITY", "address": "", "city": "", "state": "MO", "zip": "", "country": "United States", "approved": true }, "abstract": "Abstract: How the Endocytic Network Mediates Specificity of Cell Signaling Receptor crosstalk – the cooperation between two or more receptors to modulate cell responses – is a key signaling mechanism. It enables cells to generate a large combinatorial repertoire of specific signaling with a limited variety of receptors. Receptor crosstalk plays an essential role in cell physiology. Consequently, dysfunctions in receptor crosstalk are associated with many human diseases, such as infectious diseases (including COVID-19), cancer, and cardiovascular diseases. To understand the physical mechanisms by which signals from different receptors are integrated in crosstalk, studies have exclusively focused on receptor interactions at the plasma membrane. In contrast, how the crosstalk signals are transduced with high fidelity from the plasma membrane to the nucleus is poorly understood and scarcely explored. The overall goal of this research is to establish the functional role of the endocytic network in transducing and regulating receptor crosstalk. During the past 6 years, our group has made pioneering discoveries in support of the central hypothesis that the endocytic network is where extracellular chemical and physical stimuli intertwine to regulate receptor crosstalk. Specifically, we reported a new model in which receptors can crosstalk by forming overlapping interfaces between discrete signaling clusters, challenging the prevailing view that receptors oligomerize to crosstalk. Importantly, such spatially organized interaction between receptors at endosomes and plasma membranes is modulated by extracellular physical cues, and directly regulates cell inflammatory responses. These prior discoveries and the plethora of new approaches we developed for studying endosome functions laid a critical and unique foundation for us to address the knowledge gap: how does the endocytic network mediate receptor crosstalk? We will address how the endocytic network orchestrates chemical cues from receptor crosstalk (Direction 1) and transduces extracellular physical cues to refine the specificity of crosstalk signaling (Direction 2). To address the first direction, we will define the physical mechanisms by which endocytic sorting, collective endosome-organelle interactions, and endosome-specific activation modulate crosstalk signaling originated from the plasma membrane. To address the second direction, we will integrate experiments with computational modeling to determine the feedback loop between the endocytic network and cell-matrix interactions that regulate receptor crosstalk. This project will establish a mechanistic and predictive understanding of how the endocytic network mediates the spatiotemporal specificity of receptor crosstalk and cell signaling in general; a topic that is poorly understood. It will also lower the technical barrier that has impeded research on this topic, by establishing novel quantitative toolsets for dissecting the dynamics and function of the endocytic network on multiple length scales. Ultimately, a better understanding of endosome functions in receptor crosstalk will facilitate the development of new therapeutic strategies for diseases.", "keywords": [ "Address", "Autoimmune Diseases", "Biological Process", "COVID-19", "Cancer Vaccines", "Cardiovascular Diseases", "Cell Nucleus", "Cell Physiology", "Cell membrane", "Cells", "Chemicals", "Communicable Diseases", "Computer Models", "Cues", "Development", "Disease", "Endocytosis", "Endosomes", "Feedback", "Foundations", "Functional disorder", "Goals", "Immunologic Adjuvants", "Inflammatory Response", "Knowledge", "Length", "Malignant Neoplasms", "Mediating", "Mission", "Modeling", "Organelles", "Pathogenesis", "Play", "Prevention", "Public Health", "Receptor Cross-Talk", "Reporting", "Research", "Role", "Signal Transduction", "Sorting", "Specificity", "Stimulus", "United States National Institutes of Health", "cancer therapy", "combinatorial", "disease diagnosis", "endosome membrane", "experimental study", "extracellular", "human disease", "novel", "novel strategies", "novel therapeutic intervention", "receptor", "response", "spatiotemporal" ], "approved": true } } ], "meta": { "pagination": { "page": 1419, "pages": 1424, "count": 14236 } } }