Grant List
Represents Grant table in the DB
GET /v1/grants?page%5Bnumber%5D=3&sort=-id
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=-id", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1405&sort=-id", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=4&sort=-id", "prev": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=2&sort=-id" }, "data": [ { "type": "Grant", "id": "15785", "attributes": { "award_id": "1K99HL181185-01", "title": "Investigating Histone Acetylation Modulator Function in Alveolar Regeneration and Disease Pathogenesis", "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": 32586, "first_name": "ROYA", "last_name": "KALANTARI", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-01", "end_date": "2027-07-31", "award_amount": 130593, "principal_investigator": { "id": 32865, "first_name": "Dawei", "last_name": "Sun", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2649, "ror": "", "name": "BROAD INSTITUTE, INC.", "address": "", "city": "", "state": "MA", "zip": "", "country": "United States", "approved": true }, "abstract": "Influenza and COVID-19 remain significant global health concerns, with viral infections in the lungs often leading to alveolar damage and, in severe cases, progressing to acute respiratory distress syndrome (ARDS). ARDS development is closely linked to impaired alveolar regeneration, which relies on the proliferation and differentiation of alveolar type 2 (AT2) stem cells into alveolar type 1 (AT1) cells to restore lung function. The precise molecular mechanisms that govern alveolar regeneration remain poorly understood. Here I have established a high-throughput in vivo genetic screening system in mice to systematically search for essential epigenetic modulators that contribute to alveolar regeneration. Preliminary results have identified numerous histone acetylation pathway related genes, including lysine acetyltransferase 8 (Kat8), are required for AT2 restoration and may contribute to differentiation towards AT1 cells. Kat8 has not previously been linked to alveolar regeneration, however, a key component of its associated protein complex and downstream target genes has been identified in genome-wide association studies as risk genes for idiopathic pulmonary fibrosis, a deadly disease also caused by impaired alveolar regeneration. This proposal aims to clarify the mechanisms by which Kat8 regulates alveolar regeneration, determine the association of Kat8 loss of function with pulmonary fibrosis and further enhance the existing in vivo screen system by integration with single cell techniques to comprehensively map other histone acetylation modulation functions. This study will shed light on epigenetic mechanisms underlying AT2-mediated alveolar regeneration and disease pathology, with the potential to inform the design of novel therapeutic approaches targeting histone acetylation modulators to promote alveolar regeneration and combat fibrosis progression. The proposed research plan will be executed at the Broad Institute of MIT and Harvard, Cambridge, under the mentorship of Dr. Fei Chen and Dr. Jayaraj Rajagopal, with overall complementary expertise in the field of genomics, synthetic biology, and lung stem cell biology. My career objective is to become a tenure-track faculty pioneering and simultaneously training next-generation scientists at the intersection of technology and lung stem cell biology. To accomplish my career goals, I have put together a comprehensive training plan to enhance the overall skill sets required to establish myself as a successful independent investigator. To ensure timely progress toward fulfilling my rigorous research plan and career goals, I have gathered an expert advisory committee comprising Dr. Carla Kim, Dr. Darrell Kotton, Dr. Jason Buenrostro, and Dr. Ruth Franklin, with whom I will regularly discuss my research progress and receive invaluable career development guidance, the key ingredient to my pathway to scientific independence.", "keywords": [ "Acetylation", "Acetyltransferase", "Acute Respiratory Distress Syndrome", "Advisory Committees", "Alveolar", "Automobile Driving", "Biological Assay", "COVID-19", "COVID-19 mortality", "Cancer cell line", "Cell Aging", "Cell Differentiation process", "Cell Proliferation", "Cells", "Cessation of life", "Chemicals", "Complex", "Complication", "Dependovirus", "Development", "Disease", "Disease Progression", "Down-Regulation", "Engineering", "Ensure", "Epigenetic Process", "Faculty", "Fibrosis", "Gene Expression", "Genes", "Genetic", "Genetic Markers", "Genetic Screening", "Genome", "Genomics", "Goals", "Guide RNA", "Histone Acetylation", "Histone Deacetylase", "Histone H4", "Homeostasis", "Impairment", "In Vitro", "Influenza", "Knock-out", "Link", "Lung", "Lysine", "Maps", "Mediating", "Mentors", "Mentorship", "Methods", "Mitochondria", "Molecular", "Mouse Embryonic Stem Cells", "Mus", "Mutation", "Natural regeneration", "Pathogenesis", "Pathology", "Pathway interactions", "Phenotype", "Play", "Population", "Process", "Proliferating", "Pulmonary Fibrosis", "Research", "Research Personnel", "Resolution", "Role", "Satellite Viruses", "Scientist", "Stimulus", "System", "Techniques", "Technology", "Telomere Maintenance Gene", "Training", "Transitional Cell", "Variant", "Vertebral column", "Viral Pneumonia", "Virus Diseases", "career", "career development", "cell behavior", "cell type", "combat", "design", "genome wide association study", "global health", "histone acetyltransferase", "idiopathic pulmonary fibrosis", "improved", "in vivo", "insight", "loss of function", "lung injury", "lung stem cell", "male specific", "mitochondrial dysfunction", "mortality", "new therapeutic target", "next generation", "novel therapeutic intervention", "old mice", "progenitor", "protein complex", "pulmonary function", "restoration", "risk variant", "screening", "skills", "stem cell biology", "stem cells", "synthetic biology", "telomere", "tenure track", "transcriptomics" ], "approved": true } }, { "type": "Grant", "id": "15784", "attributes": { "award_id": "1R34HL177243-01A1", "title": "Empowering Cardiovascular Health in Custodial Grandparents (ECG)", "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": 32863, "first_name": "REBECCA A", "last_name": "CAMPO", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-01", "end_date": "2028-07-31", "award_amount": 197160, "principal_investigator": { "id": 32864, "first_name": "MinKyoung", "last_name": "Song", "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": "There has been a steady increase in grandparent caregiving in the US. This acceleration is due to recent trends in domestic violence, parents’ incarceration, parents’ death due to the COVID-19 pandemic, and opioid overuse that increase familial instability and leave more grandchildren to be cared for by custodial grandparents. These grandparent caregivers face ongoing stressors as they navigate legal custody arrangements, cope with loss of their own child(ren), or face social isolation. A higher prevalence in an array of social determinants of health often put them at higher risk for cardiovascular disease (CVD): belonging to a racial/ethnic minority, living below the poverty line, living in single-caregiver households, and having lower levels of educational attainment. Additionally, custodial grandparents appear to have higher rates of adverse childhood experiences, another known risk for CVD. This unique mixture of stressors manifests in custodial grandparents’ health, where they are at higher risk for CVD compared to their non-caregiving peers. However, there is a dearth of intervention addressing custodial grandparents’ CVD risk. To address this gap and optimize healthy aging and cardiovascular health among this growing at-risk population, we will implement a virtually delivered, evidence-based CVD risk reduction intervention - The Rural Caregiver Heart Health Education [RICHH] Intervention. The RICHH intervention was originally targeted for adult caregivers of adult family members with a chronic illness, and has not been tested in the context of custodial grandparents’ CVD risk. We propose a 3-year planning project to determine the feasibility, acceptability, and initial effect of the RICHH intervention conducted with custodial grandparents. We will employ a mixed method design and conduct a 2-arm randomized controlled trial with 70 custodial grandparents in Oregon. The specific aims are: 1) modify the RICHH intervention to target custodial grandparents from a variety of backgrounds; 2) employ the re-designed intervention and assess its feasibility and acceptability; and 3) evaluate and refine the RICHH protocol among our team members and explore the initial effect of the intervention based on measures of CVD risk, self- management behaviors, and depressive symptoms at 4-months and at 6-months, compared to baseline. Expected outcomes are to complete the sufficient and scientifically necessary groundwork to support a future clinical trial that will test the effectiveness of the RICHH intervention with a longer follow-up and increased inclusivity of participants from marginalized populations, with the objectives of: a) preventing CVD-related morbidity and mortality and overall physical decline, b) improving psychological well-being in these grandparents, and c) fostering a more heart-healthy environment in grandfamilies.", "keywords": [ "2 arm randomized control trial", "Acceleration", "Address", "Adherence", "Adult", "Affect", "Affective", "American", "Attitude", "Behavior", "Blood Pressure", "Body mass index", "COVID-19", "COVID-19 mortality", "COVID-19 pandemic", "Cardiac health", "Cardiovascular Diseases", "Caregivers", "Child", "Child Rearing", "Chronic Disease", "Clinical Trials", "Community Health Aides", "Custodial Care", "Data", "Data Collection", "Development", "Dietary intake", "Domestic Violence", "Educational Intervention", "Educational Status", "Effectiveness", "Environment", "Evaluation", "Face", "Family member", "Focus Groups", "Fostering", "Future", "Glycosylated hemoglobin A", "Goals", "Group Interviews", "Health", "Health education", "Heart", "High Prevalence", "Home", "Household", "Imprisonment", "Intervention", "Knowledge", "Legal", "Link", "Lipids", "Measures", "Mental Depression", "Methods", "Modification", "Morbidity - disease rate", "Oregon", "Outcome", "Parents", "Participant", "Phase III Clinical Trials", "Physical activity", "Planning Theory", "Population", "Populations at Risk", "Poverty", "Preparation", "Prevention", "Procedures", "Protocols documentation", "Public Health", "Research Design", "Research Personnel", "Risk Reduction", "Rural", "Self Care", "Self Efficacy", "Self Management", "Social isolation", "Structure", "Testing", "Trauma", "Well in self", "Work", "Writing", "acceptability and feasibility", "adverse childhood events", "cardiovascular disorder risk", "cardiovascular health", "caregiving", "coping", "data management", "depressive symptoms", "design", "effectiveness testing", "empowerment", "ethnic minority", "evidence base", "experience", "follow-up", "grandchild", "grandparent", "healthy aging", "high risk", "improved", "intervention effect", "marginalized population", "member", "mortality", "nicotine exposure", "older adult", "opioid epidemic", "opioid overuse", "opportunity cost", "peer", "post intervention", "prevent", "primary caregiver", "primary outcome", "racial minority", "recruit", "retention rate", "satisfaction", "secondary outcome", "skills", "social health determinants", "stressor", "therapy design", "treatment as usual", "trend", "virtual delivery" ], "approved": true } }, { "type": "Grant", "id": "15783", "attributes": { "award_id": "1R01AI188944-01A1", "title": "PRECISE: accessible sample-to-answer RT-PCR detection of hepatitis C infection from whole blood", "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": 32845, "first_name": "JULIE", "last_name": "DYALL", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-08", "end_date": "2030-07-31", "award_amount": 575356, "principal_investigator": { "id": 32862, "first_name": "Samuel K", "last_name": "Sia", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2647, "ror": "", "name": "COLUMBIA UNIVERSITY HEALTH SCIENCES", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true }, "abstract": "This proposal is in response to NOSI NOT-AI-23-001, which calls for new point-of-care HCV diagnostics. Most of global HCV burden is concentrated in low- and middle-income countries (LMICs), but the U.S. has witnessed a steady increase in infection rates in the past decade, with an estimated 140,000 new cases annually. Whereas direct-acting antivirals (DAAs) can over 95% of HCV-infected individuals, and are becoming more accessible, about 40% of infected people are unaware of their status. The current two-step diagnostic process requires an initial antibody screen followed by an expensive and time-consuming RNA test to confirm active infection. This cumbersome workflow requires multiple office visits for patients, resulting in delays in treatment initiation and significant patient follow-up loss. Our lab has been developing plasmonic-based thermocycling into a clinically useful method for fast multiplexed RT-PCR at the POC. In this approach, heating is achieved not externally via the Peltier effect, but rather internally via infrared excitation of nanoparticles; as a result, the heating is rapid, and powered with low- power robust optical components. We have gathered substantial preliminary data to validate the premise of this approach to work on clinical specimens (saliva and nasal swabs); the results (published in Nature Nanotechnology, 2022) showed the ability, within 25 minutes from sample to result, to detect SARS-CoV-2 with high sensitivity and specificity. Moreover, even in the presence of the plasmonic nanoparticles, we showed that real-time qPCR could be performed with accurate quantitative determinations of cycle threshold (Ct) values. This capability for sample-to-result analysis is faster than traditional PCR approaches using Peltier heating, and the instrumentation using readily available optics renders the approach suitable for community testing sites where rapid and accurate results are sought. This proposal integrates plasmonic PCR with plasma filtration (starting with whole blood) and magnetic bead-based nucleic-acid extraction (a technique we recently published called PRECISE, Lab Chip, 2024). The proposed combined method, PRECISE plasmonic PCR, takes advantage of special nanoparticles to facilitate a seamless sample-to-result workflow for the end user, suitable for the target community health settings to facilitate HCV diagnosis in a single patient visit to enable on-the-spot treatment. The target metrics would be the best in class among HCV nucleic-acid tests, meeting all of the criteria in the target product profile recommended by the NOSI for an “optimal” test except for the 15-minute turnaround time (our target is 30 minutes), and surpassing all “minimal” targets. The target metrics include cost considerations.", "keywords": [ "Accountability", "Anti-viral Agents", "Antibodies", "Benchmarking", "Biological Assay", "Blood", "Blood specimen", "COVID-19 detection", "Caring", "Clinic", "Clinical", "Collection", "Communities", "Community Health", "Consumption", "Data", "Decentralization", "Detection", "Devices", "Diagnosis", "Diagnostic", "Filtration", "HCV infection", "Health Care Surveys", "Health Personnel", "Heating", "Hepatitis C virus", "India", "Individual", "Infection", "Liver", "Magnetism", "Malignant neoplasm of liver", "Methods", "Microfluidics", "Nanotechnology", "Nature", "New Jersey", "Nucleic Acid Amplification Tests", "Nucleic Acids", "Office Visits", "Optics", "Patients", "Persons", "Phase", "Plasma", "Preparation", "Primary Care", "Process", "Publishing", "RNA", "Recommendation", "Research Institute", "Reverse Transcriptase Polymerase Chain Reaction", "Saliva", "Sampling", "Sensitivity and Specificity", "Site", "Specimen", "Spottings", "Techniques", "Technology", "Temperature", "Testing", "Time", "Training", "Tube", "United States", "Vendor", "Visit", "Whole Blood", "Work", "cost", "cost effective", "detection limit", "detection platform", "follow-up", "high risk", "improved", "infection rate", "innovation", "instrumentation", "low and middle-income countries", "magnetic beads", "meetings", "mortality", "nanoGold", "nanoparticle", "nanoshell", "nasal swab", "novel", "operation", "plasmonics", "point of care", "point of care testing", "response", "screening uptake", "skills", "usability", "user-friendly", "viral detection" ], "approved": true } }, { "type": "Grant", "id": "15782", "attributes": { "award_id": "1R01AI189398-01", "title": "Structural and mechanistic study of bat NLRP6 inflammasome in detecting RNA viruses", "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": 32860, "first_name": "KENTNER L", "last_name": "SINGLETON", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-01", "end_date": "2030-07-31", "award_amount": 451836, "principal_investigator": { "id": 32861, "first_name": "Chen", "last_name": "Shen", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2646, "ror": "", "name": "WASHINGTON UNIVERSITY", "address": "", "city": "", "state": "MO", "zip": "", "country": "United States", "approved": true }, "abstract": "Bats harbor the unique ability to host a wide array of emerging viruses, such as Ebola virus, Nipah virus, Hendra virus, and severe acute respiratory syndrome coronavirus (SARS-CoV). These RNA viruses are highly pathogenic and often lethal to humans and animals. Intriguingly, bats develop no/minimal signs of diseases in both natural and experimental infections. Significant progress has been made to suggest the altered immunological networks and dampened inflammatory signaling in bats. However, the direct viral sensing mechanisms in bats and the unique immunological features that distinguish bats from other mammals remain poorly studied. Inflammasomes are multi-protein signaling platforms that form in epithelial cells and myeloid cells upon stimulation by pathogen and damage signals. Their primary function is to active the inflammatory caspases such as caspase-1. Canonical inflammasome sensors consist mainly of nucleotide-binding domain (NBD), leucine-rich repeat (LRR)-containing (NLR) family proteins. Among these NLR proteins, NLRP6 is a unique pattern recognition receptor that is predominantly expressed in intestinal and liver system. The inflammasome function of NLRP6 has been reported to directly detect the RNA viruses (rotavirus and mouse hepatitis virus) that infect the gastrointestinal (GI) tract. On the other hand, the excessive activation of NLRP6 inflammasome may exacerbate the tissue damage and cause the autoinflammatory diseases. In bats, the GI tract represents one major organ for viral infection, while infections rarely cause symptoms. The long-term goal of our project is to understand the specific inflammasome sensing mechanisms in detecting RNA viruses in the intestinal epithelium of bats and gain the insights of how bats protect themselves from the pathogenesis of inflammation-induced intestinal barrier dysfunction. In this application, we propose to pursue the following specific aims: 1) Determine the cryo- EM structures of bat NLRP6 monomer, elucidate the biochemical foundation of bat NLRP6- dsRNA interaction, determine the cryo-EM structures of bat NLRP6 with viral dsRNA and compare the structural mechanisms of dsRNA sensing and inflammasome signaling among bat, mouse and human NLRP6; 2) Elucidate the RNA virus-induced bat NLRP6 inflammasome signaling in reconstituted intestinal epithelial cells (IECs), analyze the bat inflammasome signaling in Eonycteris spelaea (Es) in response to bat-borne RNA viruses, study the genetic role of bat NLRP6 in regulating inflammasome signaling in bat primary IECs/bat intestinal organoids. The proposed studies will guide the development of therapeutics to target GI inflammatory disorders in human based on the molecular details of bat NLRP6 inflammasome.", "keywords": [ "Address", "Affinity", "Animals", "Attention", "Binding", "Biochemical", "Biochemistry", "Biology", "Biophysics", "Blood", "Body Size", "CASP1 gene", "Caspase", "Chiroptera", "Coronavirus", "Cryoelectron Microscopy", "Data", "Development", "Diarrhea", "Disease", "Double-Stranded RNA", "Ebola virus", "Electrophoretic Mobility Shift Assay", "Enteritis", "Epithelial Cells", "Exhibits", "Flying body movement", "Foundations", "Functional disorder", "Gastrointestinal tract structure", "Genetic", "Genetic study", "Goals", "Hendra Virus", "Human", "Immune system", "Immunologics", "Immunology", "In Vitro", "Infection", "Inflammasome", "Inflammation", "Inflammatory", "Inflammatory Bowel Diseases", "Inflammatory Response", "Innate Immune System", "Interdisciplinary Study", "Intestines", "Learning", "Leucine-Rich Repeat", "Liver", "Mammals", "Maps", "Mediating", "Middle East Respiratory Syndrome", "Middle East Respiratory Syndrome Coronavirus", "Molecular", "Murine hepatitis virus", "Mus", "Myeloid Cells", "Nipah Virus", "Nucleotides", "Organ", "Organoids", "Outcome", "Pathogenesis", "Pathogenicity", "Pattern", "Pattern recognition receptor", "Play", "Protein Family", "Proteins", "RNA Virus Infections", "RNA Viruses", "Recombinants", "Reporting", "Resolution", "Role", "Rotavirus", "SARS coronavirus", "Signal Transduction", "Signaling Protein", "Structure", "Symptoms", "Syndrome", "System", "Therapeutic", "Tissues", "Viral", "Viral Load result", "Virus", "Virus Diseases", "Work", "autoinflammatory", "autoinflammatory diseases", "bat-borne", "emerging virus", "experimental study", "gastrointestinal", "gastrointestinal system", "insight", "intestinal barrier", "intestinal epithelium", "life span", "metabolic rate", "monomer", "novel therapeutics", "pathogen", "prevent", "reconstitution", "response", "restraint", "sensor", "therapeutic development", "viral RNA" ], "approved": true } }, { "type": "Grant", "id": "15781", "attributes": { "award_id": "1R01AI183979-01A1", "title": "Expanding access and impact of tuberculosis preventive therapy: Community-friendly delivery and monitoring of TPT to improve uptake and reduce TB transmission", "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": 32562, "first_name": "KAREN A", "last_name": "LACOURCIERE", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-19", "end_date": "2030-07-31", "award_amount": 690538, "principal_investigator": { "id": 28321, "first_name": "ADRIENNE E", "last_name": "SHAPIRO", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2645, "ror": "", "name": "UNIVERSITY OF WASHINGTON", "address": "", "city": "", "state": "WA", "zip": "", "country": "United States", "approved": true }, "abstract": "Enter the text here that is the new abstract information for your application. International and Kenyan guidelines recommend TB preventive therapy (TPT) for people with HIV (PWH) and other people at high risk for TB, including close contacts of people with TB. Despite the evidence for reduced morbidity and mortality for people with HIV (PWH) who receive TPT, and guidelines recommending use, there remains a substantial gap between people recommended to receive and people who actually receive and complete a course of TPT. The 2022 WHO Global TB Report highlighted the growing gap in access and provision of TPT, which has been aggravated by the COVID-19 pandemic. Bridging this gap is a Kenyan and global priority. With the recent availability and evidence for newer, shorter regimens of TPT, a transformation of HIV care delivery models (in part forced by the COVID-19 pandemic) and evolving national guidelines for TPT, it is increasingly urgent to explore new person-friendly models of TPT delivery to inform programmatic guidance that results in greater uptake, adherence, and completion of TPT. HIV care transformed to adopt “differentiated service delivery” (DSD) models, which encourage community-delivered care, infrequent clinic/facility visits, multi- month dispensing, limited laboratory monitoring, and task-shifted treatment models to deliver comprehensive HIV care to stable adults in community settings. These successful models for differentiated HIV care delivery may be able to be adapted to include TPT. The availability of safe, effective, short-course TPT (i.e. 3HP, 3HR) with limited monitoring requirements suggests that similar community-based and multi-month dispensing models may be adapted to scale essential TPT to populations who most need it, including PWH, young child contacts, and all household contacts of people with TB. We will explore two approaches of adapting HIV differentiated services to TB prevention. We hypothesize that people who receive differentiated TPT delivery have higher rates of completion of a course of TPT than people who receive standard-of-care clinic-based TPT. We will 1) conduct a randomized controlled trial of DSD care (multi-month dispensing) vs. clinic standard-of-care TPT delivery in two priority populations for TPT in Kenya: household contacts of people with TB and PWH, 2) investigate the impact of DSD TPT on household and community TB transmission with follow-up testing and mathematical modeling, and 3) examine preferences, barriers and facilitators of TPT completion and TPT implementation using qualitative research. Together, this research will establish the foundation for implementation studies of optimized patient and community-friendly, differentiated TPT delivery approaches to increase TPT uptake and completion in Kenya and ultimately decrease morbidity, transmission, and mortality from TB.", "keywords": [ "Adherence", "Adopted", "Adult", "Adverse effects", "Biological Assay", "COVID-19 pandemic", "Caring", "Cessation of life", "Child", "Client", "Clinic", "Clinical", "Communicable Diseases", "Communities", "Dose", "Drug resistance in tuberculosis", "Eligibility Determination", "Focus Groups", "Foundations", "Friends", "Goals", "Guidelines", "HIV", "HIV/TB", "Health system", "Home", "Household", "Incidence", "Individual", "Interferon Type II", "International", "Interview", "Kenya", "Laboratories", "Measures", "Methodology", "Methods", "Modeling", "Monitor", "Morbidity - disease rate", "Patients", "Persons", "Pharmaceutical Preparations", "Population", "Prevention", "Preventive therapy", "Qualitative Research", "Randomized", "Randomized Controlled Trials", "Recommendation", "Regimen", "Reporting", "Research", "Schedule", "Service delivery model", "Services", "Testing", "Text", "Time", "Toxic effect", "Travel", "Treatment Protocols", "Tuberculosis", "Tuberculosis diagnosis", "Visit", "World Health Organization", "care delivery", "community setting", "cost", "experience", "follow-up", "gaps in access", "health care delivery", "high risk", "immunoreactivity", "implementation strategy", "implementation study", "improved", "informant", "innovation", "isoniazid", "mathematical model", "mortality", "person centered", "pill", "preference", "prevent", "preventable death", "rifapentine", "scale up", "screening", "service delivery", "standard of care", "supply chain", "transmission process", "treatment as usual", "trial comparing", "uptake" ], "approved": true } }, { "type": "Grant", "id": "15780", "attributes": { "award_id": "1R01CA293884-01A1", "title": "The impact of dyadic processes on smoking and cigarette craving: An experimental investigation of romantic partners and smoking friends", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Cancer Institute (NCI)" ], "program_reference_codes": [], "program_officials": [ { "id": 32857, "first_name": "REBECCA", "last_name": "FERRER", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-07", "end_date": "2029-07-31", "award_amount": 2202321, "principal_investigator": { "id": 32858, "first_name": "Amanda", "last_name": "Forest", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32859, "first_name": "MICHAEL Andrew", "last_name": "SAYETTE", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 2644, "ror": "", "name": "UNIVERSITY OF PITTSBURGH AT PITTSBURGH", "address": "", "city": "", "state": "PA", "zip": "", "country": "United States", "approved": true }, "abstract": "Smoking is the leading preventable cause of cancer and mortality in the US, with Covid hitting smokers especially hard. Quitting is difficult (and smoking increased during Covid), yet interventions yield only mixed success. Smokers often smoke and crave cigarettes in social settings. Public health research emphasizes social factors in smoking, and clinical studies point to the need to better understand disrupted relationship dynamics when a romantic partner or friend quits. Thus, it is striking that nearly all lab research (testing causal relations) on smoking and craving tests smokers in isolation. This neglect of social factors extends to quitting practices. Even on the most respected websites, the “social” advice for quitting offers fairly simplistic and incomplete tips that fail to consider subtle yet powerful challenges that quitting may create for smoking friends and romantic partners. Further, there is no evidence regarding how social factors exacerbate the altered smoking-related decision-making that accompanies craving, thus raising the likelihood of smoking. To develop a comprehensive understanding of the factors and processes that maintain smoking and increase relapse risk, basic experimental research that integrates social processes into existing paradigms focusing on pharmacologic and (individual) psychological aspects of addiction is needed. This basic experimental study with humans (BESH) application addresses targeted NCI Behavioral Research Program priorities focused on leveraging research on dyadic processes to examine health-related behaviors such as smoking cessation. Integrating theory and research derived from three disciplines rarely applied to smoking (experimental social psychology with a focus on dyadic processes, affective science, cognition), the project will offer a multimodal analysis of craving and smoking in two social contexts relevant to smoking (friendships, romantic couples). This project will use innovative measures of affect (e.g., an urge pressure dynamometer, speech volume, Facial Action Coding System) and decision-making to test theoretically-derived processes (e.g., shared reality, motivated reasoning, emotional contagion) that may help explain the challenges linked to quitting when rewarding social aspects of smoking are lost. The project will elucidate why some smokers may struggle managing relationships when quitting, and why social interventions may be most useful for a subset of smokers. In both a friends study and a couples study, abstinent daily and nondaily smokers will be recruited. The friends study will test the impact of a friend’s presence on cue-elicited craving, with a focus on shared craving states, and the couples study will target effects of mutual smoking versus unilateral smoking on critical social interactions and relationship perceptions thought to raise obstacles to quitting. This project will test important social-cognitive and socio- emotional mechanisms underlying craving and smoking that may identify hidden social motives for smoking that must be integrated into biopsychosocial smoking treatment. Regardless of outcome, this work will provide valuable data on emotional and cognitive processes experienced in social settings during craving and smoking.", "keywords": [ "Acoustics", "Address", "Affect", "Affective", "American", "Behavioral Research", "Cancer Etiology", "Cessation of life", "Cigarette", "Clinical", "Clinical Research", "Code", "Cognition", "Cognitive", "Couples", "Cues", "Data", "Decision Making", "Discipline", "Disclosure", "Electronic cigarette", "Emotional", "Emotions", "Event", "Face", "Friends", "Friendships", "Future", "Goals", "Health", "Health behavior", "Human", "Individual", "Intervention", "Investigation", "Language", "Link", "Malignant Neoplasms", "Measures", "Methodology", "Methods", "Modeling", "Monitor", "Nicotine", "Nicotine Dependence", "Outcome", "Patient Self-Report", "Perception", "Persons", "Pharmaceutical Preparations", "Play", "Preventable cancer cause", "Process", "Public Health", "Reporting", "Research", "Rewards", "Role", "Science", "Smiling", "Smoke", "Smoker", "Smoking", "Smoking treatment", "Social Environment", "Social Interaction", "Social Processes", "Social Psychology", "Speech", "Subgroup", "Testing", "Tobacco", "Treatment Efficacy", "Work", "addiction", "biopsychosocial", "cigarette craving", "cigarette smoking", "cognitive process", "contagion", "craving", "experience", "experimental study", "heuristics", "innovation", "insight", "member", "mortality", "multimodality", "neglect", "novel", "pharmacologic", "premature", "pressure", "prevent", "programs", "psychologic", "public health research", "recruit", "relapse risk", "smoking cessation", "smoking cue", "social", "social factors", "social interventions", "social relationships", "success", "theories", "web site" ], "approved": true } }, { "type": "Grant", "id": "15779", "attributes": { "award_id": "1R01AI197146-01", "title": "SCH: A structural causal framework for adaptive experiments", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "NIH Office of the Director" ], "program_reference_codes": [], "program_officials": [ { "id": 32567, "first_name": "MEGHAN ANN", "last_name": "HARTWICK", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-06", "end_date": "2029-07-31", "award_amount": 299422, "principal_investigator": { "id": 32855, "first_name": "Ivan", "last_name": "Diaz", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32856, "first_name": "Michele", "last_name": "Santacatterina", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 2643, "ror": "", "name": "NEW YORK UNIVERSITY SCHOOL OF MEDICINE", "address": "", "city": "", "state": "NY", "zip": "", "country": "United States", "approved": true }, "abstract": "Adaptive randomized clinical trials are critical in infectious disease research, offering flexibility to adjust sample sizes, introduce new interventions, discontinue ineffective treatments, and target specific subgroups to enhance treatment efficacy. This adaptability is particularly valuable in rapidly evolving public health crises, such as the development of treatments for emerging infectious diseases like COVID-19. However, adaptive trials present significant challenges, including unclear inferential targets, statistical biases from temporal and spatial variability, complexities in handling dynamic data structures, and an increased risk of false-positive findings. These concerns are reflected in recent FDA guidance on estimands, which emphasizes the need for clearly defined inferential targets, and on adaptive designs, which acknowledges that statistical bias in adaptive trials remains an understudied issue. Despite these recognized challenges, current research lacks a principled framework for structurally representing and unbiasedly estimating causal effects in adaptive trials. This project will develop a structural causal framework for adaptive trials, leveraging modern causal inference and statistical techniques alongside secondary data from the Adaptive COVID-19 Treatment Trial (ACTT)—an adaptive trial evaluating novel therapeutics in hospitalized COVID-19 patients—to enable transparent, efficient, and statistically unbiased estimation of causal effects. To achieve this, we propose the following specific aims: Aim 1: Develop a structural causal approach that deals with temporal variability. Aim 2: Extend our framework to handle spatial variability. Aim 3: Expand our framework to handle complex data structures, including failure-time and missing data, while dealing with false-positive results. Our project aligns with NIAID’s mission by advancing key methodologies for infectious disease clinical trials, particularly in adaptive designs for pandemic response, emerging pathogens, and the development of antiviral treatments. While our primary focus is on infectious disease trials, our methods have broader applicability to other disease areas, such as schizophrenia. We show this by also leveraging secondary data from schizophrenia studies, including the DECIFER trial, the RAISE study, and the EPINET study. RELEVANCE (See instructions): This research aims to improve how adaptive clinical trials are designed and analyzed. By developing methods that address key challenges in adaptive trials, our work will help ensure more accurate and reliable results, ultimately leading to better treatments and public health responses to emerging infectious diseases.", "keywords": [ "Address", "Area", "COVID-19", "COVID-19 patient", "COVID-19 treatment", "Clinical Trials", "Clinical Trials Design", "Communicable Diseases", "Data", "Disease", "Emerging Communicable Diseases", "Ensure", "Failure", "Hospitalization", "Infectious Diseases Research", "Instruction", "Intervention", "Methodology", "Methods", "Mission", "Modernization", "National Institute of Allergy and Infectious Disease", "Public Health", "Reliability of Results", "Research", "Risk", "Sample Size", "Schizophrenia", "Statistical Bias", "Structure", "Subgroup", "Techniques", "Time", "Treatment Efficacy", "Work", "antiviral drug development", "complex data", "design", "emerging pathogen", "experimental study", "flexibility", "improved", "ineffective therapies", "novel therapeutics", "pandemic response", "randomized clinical trials", "response", "spatiotemporal", "therapy development", "treatment trial" ], "approved": true } }, { "type": "Grant", "id": "15778", "attributes": { "award_id": "1R50CA305057-01", "title": "A System to Support Development and Success of NCI-Sponsored Trials for Rare Diseases", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Cancer Institute (NCI)" ], "program_reference_codes": [], "program_officials": [ { "id": 32853, "first_name": "SONYA", "last_name": "ROBERSON", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-11", "end_date": "2030-07-31", "award_amount": 122610, "principal_investigator": { "id": 32854, "first_name": "Kim A", "last_name": "Reiss Binder", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 2627, "ror": "", "name": "UNIVERSITY OF PENNSYLVANIA", "address": "", "city": "", "state": "PA", "zip": "", "country": "United States", "approved": true }, "abstract": "R50 Abstract – Reiss Gastrointestinal maligancies remain lethal and difficult-to-treat, with poor outcomes for many patients. In spite of this, we are in a moment of a scientific and clinical revolution with the development of biomarker-driven therapies for selected patients. With these advances come multiple new questions for the field, many of which the NCTN infrastructure is optimally suited to address. To date, I have demonstrated a strong commitment to clinical and translational research for populations of patients with rare subsets or biomarkers, including via the development and implementation of NCI-trials at my own institution: I am the international study chair and lead accruer for EA2192 as well as the study champion and lead national accruer for SWOG-2001. On the larger scale, I hold leadership roles within the Abramson Cancer Center (ACC) at the University of Pennsylvania and at the NCTN. I serve as the co-chair of the ECOG- ACRIN GI Committee, I am the co-leader of the ACC Cancer Therapeutics Program and I am the co-leader of the ACC Pancreatic Clinical Trial Program. These leadership positions are optimal platforms upon which to spearhead programs that (1) formally and longitudinally assist junior and mid-career oncology faculty in their quests to develop investigator-initiated studies and (2) develop a program at the NCTN that focuses on developing realistic trials for rare populations and then on accruing them successfully. To date, I have demonstrated a persistent and strong commitment to the NCI research enterprise. I have been involved with NCI-related research since my early career, initially attending meetings and later developing my own protocol, EA2192. Based on my steady engagement and input, I was appointed as the co-chair of the GI Committee in 2022 alongside Jordan Berlin (see LOS). Together, we have made a commitment to improving the process of clinical trial development, a mission that will be critical in order for the NCTN to remain competitive in an ever-changing landscape. Over the past three years, we have employed multiple initiatives including boosting the education of our investigators about the NCTN process, leaning on the excellent Working groups chairs to fine-tune concepts prior to Committee Presentation and providing substantial assistance during the submission process. With the support of the R50 Research Specialist award, I will build further on this approach in two ways: At the ACC, I will develop a sustainable program for early and mid-career investigators to provide longitudinal support in the development of investigator-initiated trials, with a particular focus on rare disease studies that can be best executed via the ECOG-ACRIN system. Within the NCTN, I will employ a novel program assisting investigators in the development and successful enrollment of trials for rare disease populations, a subset of studies that have lost ground since the COVID pandemic. Specifically, I will create a living resource for NCTN investigators that focuses on methods to design practical, feasible studies and will provide longitudinal support to those across the NCTN who are developing studies in this space. My ultimate goal is to develop and implement pragmatic clinical trials that address key questions in the field of gastrointestinal malignancies, particularly for patients with rare subsets of disease.", "keywords": [ "Abramson Cancer Center at the University of Pennsylvania", "Address", "American College of Radiology Imaging Network", "Award", "Berlin", "Biological Markers", "COVID-19 pandemic", "Cancer Biology", "Cancer Center", "Clinical", "Clinical Research", "Clinical Trials", "Development", "Disease", "Eastern Cooperative Oncology Group", "Education", "Faculty", "Feasibility Studies", "Genomics", "Goals", "Infrastructure", "Institution", "International", "Jordan", "Knowledge", "Lead", "Leadership", "Malignant Neoplasms", "Malignant neoplasm of gastrointestinal tract", "Methods", "Mission", "Oncology", "Outcome", "Pancreas", "Patient Selection", "Patients", "Persons", "Population", "Positioning Attribute", "Pragmatic clinical trial", "Process", "Program Sustainability", "Protocols documentation", "Rare Diseases", "Research", "Research Personnel", "Resources", "Role", "Selection for Treatments", "Southwest Oncology Group", "Specialist", "System", "Therapeutic", "Thinness", "Translational Research", "biomarker development", "biomarker driven", "cancer subtypes", "career", "design", "gastrointestinal", "improved outcome", "investigator-initiated trial", "meetings", "novel", "patient population", "process improvement", "programs", "success", "trial enrollment", "working group" ], "approved": true } }, { "type": "Grant", "id": "15777", "attributes": { "award_id": "1R01AR085033-01", "title": "Improving the diagnosis and outcome of diffuse alveolar hemorrhage in systemic lupus erythematosus", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [ "National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)" ], "program_reference_codes": [], "program_officials": [ { "id": 32850, "first_name": "MARIE", "last_name": "MANCINI", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-06", "end_date": "2030-06-30", "award_amount": 538755, "principal_investigator": { "id": 32851, "first_name": "WESTLEY H", "last_name": "REEVES", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [ { "id": 32852, "first_name": "Haoyang", "last_name": "Zhuang", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 2642, "ror": "", "name": "UNIVERSITY OF FLORIDA", "address": "", "city": "", "state": "FL", "zip": "", "country": "United States", "approved": true }, "abstract": "The variable clinical manifestations of SLE patients are largely unexplained. Although severe diffuse alveolar hemorrhage (DAH) with pulmonary capillaritis is unusual in lupus, more than half of patients with this complication die and focal lung hemorrhage occurs in 30-66% of patients. Using a mouse model (pristane-induced lupus) developed in our laboratory, we will ask why C57BL/6 (B6) mice are susceptible to pristane-induced DAH/vasculitis whereas BALB/c and DBA/2 mice are resistant. DAH is initiated by lung endothelial cell (EC) injury followed by recruitment of bone marrow-derived monocytes to the lung. We found that dysregulation of the extrinsic coagulation pathway also is involved and that lung disease is abolished by early treatment with MEK1/2 or ERK1/2 inhibitors. The overall hypothesis is that genetically- determined lung microvascular EC injury evolves into DAH because of monocyte infiltration into the lung and abnormal regulation of the extrinsic coagulation pathway. Aim 1 addresses susceptibility to DAH. We will ask whether EC injury and bleeding are lung-specific and investigate gene expression patterns associated with DAH by single-cell RNA-sequencing. Genes conferring susceptibility/resistance to EC injury and bleeding be mapped in recombinant inbred BXD (B6 X D2) mice. Aim 2 examines the MEK1/2-ERK1/2 pathway in pristane-induced DAH. We will define the sequence of events leading to DAH and develop blood-based diagnostic tests for the diagnosis of incipient DAH prior to the onset of bleeding. This is important, because the disease process is irreversible once hemorrhage begins. We will look for tests that distinguish early DAH (pre-bleeding) from other forms of lung injury, such as sepsis with acute respiratory distress syndrome. Aim 3 translates what is learned in mice to human DAH. We hypothesize that the disease process is similar except that the initial EC injury is caused by respiratory viral infections rather than pristane. We will ask if a predisposition to lung EC injury determines susceptibility, as in mice, and whether diagnostic approaches developed in the mouse model are relevant to human DAH. Lung EC injury will be examined in SLE patients with influenza or COVID infection and the role of mild bleeding disorders will be explored. The ability to diagnose incipient DAH (pre- bleeding) may permit future therapeutic trials using FDA-approved MEK1/2 inhibitors, such as trametinib, which are highly effective in pristane-induced DAH.", "keywords": [ "ANCA vasculitis", "Acute Respiratory Distress Syndrome", "Address", "Adopted", "Alveolar", "Antineutrophil Cytoplasmic Antibodies", "Autoantibodies", "Autoimmune", "Autoimmune Diseases", "BALB/cJ Mouse", "Biological Assay", "Blood", "Blood Coagulation Disorders", "Blood Vessels", "Bone Marrow", "C57BL/6 Mouse", "COPA syndrome", "Cell Line", "Clinical", "Coagulation Process", "Complex", "Complication", "DBA/2 Mouse", "Data", "Defect", "Dependence", "Development", "Diagnosis", "Diagnostic tests", "Diffuse", "Disease", "Disease susceptibility", "Early Diagnosis", "Early treatment", "Endothelial Cells", "Environmental Risk Factor", "Enzyme-Linked Immunosorbent Assay", "Event", "Exanthema", "Exhibits", "FDA approved", "Future", "Gene Expression", "Gene Expression Profile", "Genes", "Genetic", "Genetic Predisposition to Disease", "Hemorrhage", "Hemostatic function", "Human", "Immune", "Immunologics", "Inbred BALB C Mice", "Inbreeding", "Infiltration", "Inflammation", "Inherited", "Injury", "Intervention", "Kidney", "Laboratories", "Learning", "Life", "Link", "Lung", "Lung Diseases", "Lupus", "Lupus Nephritis", "MAP2K1 gene", "MAPK3 gene", "Malignant Neoplasms", "Maps", "Mediating", "Mitogen-Activated Protein Kinases", "Modeling", "Monitor", "Mouse Strains", "Mus", "NUP214 gene", "Outcome", "Pathogenesis", "Pathway interactions", "Patients", "Plasma", "Predisposition", "Pristane", "Process", "Prognosis", "Public Health", "Qualifying", "Recombinants", "Regulation", "Resistance", "Respiratory Tract Infections", "Retinal blind spot", "Role", "SARS-CoV-2 infection", "Sepsis", "Serum", "Severity of illness", "Systemic Lupus Erythematosus", "Testing", "Therapeutic Trials", "Tissues", "Translating", "Vascular Diseases", "Vasculitis", "Viral Respiratory Tract Infection", "cell injury", "diagnostic strategy", "ds-DNA", "experience", "genome wide association study", "immune function", "improved", "influenza infection", "inhibitor", "injured", "lung injury", "lung microvascular endothelial cells", "monocyte", "mouse model", "novel therapeutics", "prevent", "protein expression", "pulmonary", "recruit", "sepsis induced ARDS", "single-cell RNA sequencing", "treatment response" ], "approved": true } }, { "type": "Grant", "id": "15776", "attributes": { "award_id": "1R35GM160065-01", "title": "Statistical Approaches to Unlock Protein Function from Deep Mutational Scans", "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": 32565, "first_name": "GUOQIN", "last_name": "YU", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "start_date": "2025-08-01", "end_date": "2030-07-31", "award_amount": 420984, "principal_investigator": { "id": 32849, "first_name": "Harold", "last_name": "Pimentel", "orcid": "", "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] }, "other_investigators": [], "awardee_organization": { "id": 818, "ror": "", "name": "UNIVERSITY OF CALIFORNIA LOS ANGELES", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "Understanding how genetic variants impact protein function is essential for unraveling the mechanisms underlying both basic biology and disease, particularly for rare genetic variants. Of the 4.6 million missense variants found in large population studies, only about 2% have clinical interpretations. Due to their rarity, these variants are exceptionally challenging to study through observational methods. However, Deep Mutational Scanning (DMS) offers a high-throughput method for testing thousands of protein variants by generating a mutant library and obtaining a phenotypic readout for each mutation in one sequencing assay. Initially focused on fitness-based readouts, DMS has expanded to include fluorescence-based methods for protein profiling, binding assays, and more. It has been crucial for studying proteins like SARS-CoV-2, BRCA1, and drug-metabolism transporters like OCT1. With over 1,000 protein datasets publicly available, a recent study highlights technical advances by independently assaying over 500 additional proteins in one study. Unfortunately, the development of statistical methods to interpret and analyze these technologies has not kept pace. For example, DMS with fluorescence-activated cell sorting (DMS-FACS), which has been used for nearly a decade to measure protein abundance and other functional phenotypes, still lacks dedicated analysis methods. As a result, analyses are often ad hoc, and small sample sizes (typically three replicates) make standard statistical methods unsuitable. Our recent work demonstrates that naive approaches miss many real effects and lead to many false discoveries. We propose three statistical areas to improve DMS analysis and interpretation through accurate sample comparisons, epistasis analysis, and causal inference. First, we will develop methods to analyze DMS-FACS for assessing how genetic variants affect molecular phenotype targeted by FACS, and enabling precise comparisons between experimental conditions. Second, we will develop methods to improve genetic interaction (epistasis) analysis and interpretation within proteins, and thus ask which protein regions are acting in concert. Third, we open a new area of research for DMS, aiming to identify the causal impact of variants through measured pathways, including complex traits. In summary, we will solve the analysis gap for DMS-FACS, epistasis DMS, and causally link DMS data through structural causal models by leveraging our expertise in DMS data and small sample statistics. Leveraging our expertise in DMS data and small sample statistics, we will create reliable, robust tools for common workflows while also enabling new types of analyses that improve the interpretation of DMS, epistasis, and phenotypic relationships. With strong collaborations with assay developers and DMS experts, along with a proven track record in developing tools for high-throughput sequencing in small sample contexts, we are well-positioned to lead this effort.", "keywords": [ "2019-nCoV", "Affect", "Area", "BRCA1 gene", "Binding", "Biological Assay", "Biology", "Clinical", "Collaborations", "Complex", "Data", "Data Analyses", "Data Set", "Dedications", "Development", "Disease", "Fluorescence", "Fluorescence-Activated Cell Sorting", "Genetic", "Genetic Epistasis", "High-Throughput Nucleotide Sequencing", "Lead", "Libraries", "Link", "Measures", "Methods", "Missense Mutation", "Molecular", "Mutation", "Pathway interactions", "Phenotype", "Population Study", "Positioning Attribute", "Protein Region", "Proteins", "Research", "Sample Size", "Sampling", "Statistical Methods", "Statistical Models", "Technology", "Testing", "Variant", "Work", "causal model", "drug metabolism", "fitness", "genetic variant", "improved", "molecular phenotype", "mutant", "mutation screening", "protein function", "protein profiling", "statistics", "tool", "trait" ], "approved": true } } ], "meta": { "pagination": { "page": 3, "pages": 1405, "count": 14046 } } }