Grant List
Represents Grant table in the DB
GET /v1/grants?page%5Bnumber%5D=1383&sort=-award_amount
{ "links": { "first": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1&sort=-award_amount", "last": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1397&sort=-award_amount", "next": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1384&sort=-award_amount", "prev": "https://cic-apps.datascience.columbia.edu/v1/grants?page%5Bnumber%5D=1382&sort=-award_amount" }, "data": [ { "type": "Grant", "id": "6723", "attributes": { "award_id": "5I01BX005466-02", "title": "Covid-19: Fast-tracking treatment by exploiting the steroid hormone receptor/TMPRSS2 axis", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [], "program_reference_codes": [], "program_officials": [], "start_date": "2021-04-01", "end_date": "2023-03-31", "award_amount": null, "principal_investigator": { "id": 22480, "first_name": "Kerry L.", "last_name": "Burnstein", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1500, "ror": "", "name": "MIAMI VA HEALTH CARE SYSTEM", "address": "", "city": "", "state": "FL", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1500, "ror": "", "name": "MIAMI VA HEALTH CARE SYSTEM", "address": "", "city": "", "state": "FL", "zip": "", "country": "United States", "approved": true }, "abstract": "COVID-19 poses a tremendous health threat, particularly to individuals overrepresented in the US Veteran community. COVID-19 mortality is greater in men than in women; while this disparity is at least partially due to factors such as higher rates of smoking, a hormonal link is likely and can be rapidly tested therapeutically by repurposing existing drugs. The viral etiologic agent of COVID-19, SARS-CoV-2 (CoV-2), attaches to human airway epithelium via the viral spike (S) protein, which binds to angiotensin-converting enzyme 2 (ACE2) on the host cell surface. Viral entry requires S protein cleavage by the serine protease TMPRSS2, which is a known transcriptional target of the androgen receptor (AR). Lung epithelial cells (a target of CoV-2 infection) express transcriptionally active AR. We hypothesize that AR up-regulates TMPRSS2 in lung epithelial cells and thereby promotes viral entry and infectivity. We propose that FDA-approved AR antagonists will decrease CoV-2 entry and spread and can be rapidly repurposed for COVID-19. IL-6 is the major cytokine released in moderate and severe COVID-19 cases and both published and our preliminary data show that IL-6 enhances AR transcriptional activity. We will therefore also examine the contribution of interleukin 6 (IL-6) to AR regulation of TMPRRS2. To facilitate these studies in a robust manner, we propose to isolate the SARS-CoV-2 entry mechanism through the use of luciferase-expressing pseudovirions that harbor the SARS-CoV-2 S protein. Such a reporter system has high reproducibility, versatility and dynamic range, allowing for the rapid, accurate and specific assessment of a large range of viral entry regulators into primary human lung epithelial cells and lung adenocarcinoma cell lines under BSL2+ conditions. We will test whether AR inhibition reduces TMPRSS2 and the requisite S protein processing thereby decreasing CoV-2 entry into host lung epithelial cells. Subsequently, we will confirm results on a subset of promising compounds using live SARS-Cov-2 in an approved BSL3 facility. Safe and effective AR antagonists are FDA approved for prostate cancer and this study will provide rationale to repurpose these drugs for use in clinical trials for COVID-19. The glucocorticoid receptor (GR) shares a common DNA response element consensus sequence with AR. Furthermore, GR upregulation of TMPRSS2 has been shown in advanced prostate cancer. Therefore, in parallel, we will examine whether TMPRSS2 is regulated by glucocorticoids (cortisol) and blocked by a GR antagonist in models of human lung epithelia. Patients taking corticosteroids (including the elderly and individuals with diabetes, hypertension and chronic inflammatory disease) are at the highest risk of death from COVID-19. The World Health Organization has provided interim guidance to avoid glucocorticoids in COVID- 19 patients with severe acute respiratory distress syndrome. Therefore, understanding GR regulation of TMPRSS2 is also essential to repurposing the TMPRSS2-inhibitory FDA-approved agents for COVID-19. Our aims are to: (1) Evaluate steroid hormone receptor (AR and GR) regulation of TMPRSS2 in human primary airway and lung epithelial cells and lung adenocarcinoma cell line models and (2) Examine the capacity of FDA-approved AR and GR antagonists to block CoV-2 entry and infectivity in human primary airway and lung epithelial cells. US Veterans represent several demographics acutely afflicted by COVID-19. Older US Veterans are particularly vulnerable because of higher comorbidities including smoking, diabetes, heart disease and hypertension. Burden on the Veteran community is also proportionally higher given the propensity for poor outcome in men as compared to women following COVID-19 infection. Since the anti-androgen therapies to be tested are FDA approved for prostate cancer treatment and have also been used safely in women with breast cancer, our study has potential for immediate impact to all veterans.", "keywords": [ "2019-nCoV", "ACE2", "Acute", "Acute Respiratory Distress Syndrome", "Address", "Adrenal Cortex Hormones", "Affect", "Agonist", "Androgen Antagonists", "Androgen Receptor", "Antiandrogen Therapy", "Binding", "COVID-19", "COVID-19 mortality", "COVID-19 patient", "COVID-19 treatment", "Cell Line", "Cell surface", "Clinical Trials", "Collaborations", "Colorado", "Communities", "Consensus Sequence", "DNA", "Data", "Diabetes Mellitus", "Disease", "Drug usage", "Elderly", "Enrollment", "Epithelial", "Epithelial Cells", "Etiology", "FDA approved", "Genetic Transcription", "Glucocorticoid Receptor", "Glucocorticoids", "Health", "Health Personnel", "Heart Diseases", "Hormonal", "Human", "Hydrocortisone", "Hypertension", "Individual", "Infection", "Interdisciplinary Study", "Interleukin-6", "Ligands", "Link", "Luciferases", "Lung", "Lung Adenocarcinoma", "Malignant neoplasm of prostate", "Measures", "Modeling", "Nuclear Receptors", "Outcome", "Patients", "Pattern", "Pharmaceutical Preparations", "Pharmacological Treatment", "Prostate Cancer therapy", "Proteins", "Proteolysis", "Publishing", "Receptor Inhibition", "Regulation", "Reporter", "Reproducibility", "Research", "Resistance", "Response Elements", "SARS-CoV-2 infection", "SARS-CoV-2 spike protein", "Serine Protease", "Smoking", "Stanolone", "System", "TMPRSS2 gene", "Testing", "Therapeutic", "Universities", "Veterans", "Viral", "Virus", "Woman", "World Health Organization", "advanced prostate cancer", "airway epithelium", "biosafety level 3 facility", "castration resistant prostate cancer", "chronic inflammatory disease", "comorbidity", "cytokine", "demographics", "drug repurposing", "glucocorticoid receptor alpha", "high risk", "human model", "loved ones", "mRNA Expression", "male", "malignant breast neoplasm", "men", "protein expression", "receptor upregulation", "response", "severe COVID-19", "steroid hormone receptor", "therapeutic evaluation", "transcriptome", "viral entry inhibitor" ], "approved": true } }, { "type": "Grant", "id": "6757", "attributes": { "award_id": "5I01BX005432-02", "title": "COVID-19: Elucidating the Role of the NasalEpithelium in SARS-CoV-2 Infection, Transmission, and Prevention", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [], "program_reference_codes": [], "program_officials": [], "start_date": "2021-01-01", "end_date": "2022-12-31", "award_amount": null, "principal_investigator": { "id": 22556, "first_name": "Noam A", "last_name": "Cohen", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1488, "ror": "https://ror.org/03j05zz84", "name": "Philadelphia VA Medical Center", "address": "", "city": "", "state": "PA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1488, "ror": "https://ror.org/03j05zz84", "name": "Philadelphia VA Medical Center", "address": "", "city": "", "state": "PA", "zip": "", "country": "United States", "approved": true }, "abstract": "Severe acute respiratory syndrome coronavirus SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19) has led to a pandemic with a mortality of approximately 3.5% and a wide range of morbidity outcomes negatively impacted by pre-existing conditions. Given the prevalence of pre-existing comorbid conditions in Veterans, it is imperative to understand the mechanisms of how SARS-CoV-2 invades and replicates within the barrier defense cells of the nose, which is the primary portal for viral entry. Furthermore, current data suggests that the nasal carriage functions as a potential reservoir for viral persistence and transmission (i.e., shedding) at times that are both prior to and during the manifestation of severe respiratory symptoms. This project utilizes a unique biobank of cryopreserved nasal cells collected from over 1000 individuals over 15 years to understand the critical issues surrounding SARS-CoV-2 interaction with the human nasal epithelia. Paradoxically, while SARS-CoV-2 can be detected in nasal swabs prior to its detection in sputum, there is a paucity of rhinologic symptoms (<5% with nasal congestion) associated with COVID-19, with the exception of reversible anosmia in 30-70% of patients. This is particularly problematic because up to 25% of infected individuals remain asymptomatic, but can continue to spread SARS-CoV-2 through airborne droplets. This work seeks to elucidate both the mechanisms controlling which epithelial cell lineages become infected with virus and the type of immune response generated within infected or neighboring epithelia. Through this approach, we will shed light on the issue of why certain individuals never develop symptoms while others progress to severe respiratory failure and death. We will focus on the SARS-CoV-2 receptor Angiotensin Converting Enzyme 2 (ACE2), which is essential and sufficient for the virus to enter cells. Our preliminary data generated from single cell RNA analysis of primary human sinonasal tissue demonstrates that ACE2 is expressed in discrete clusters of nasal epithelia. ACE2- specific immunostaining of human nasal epithelial cells ex vivo and primary ciliated air liquid interface (ALI) cultures corroborates the sc-RNAseq data. Furthermore, our data show that inoculation of primary ALI cultures with SARS-CoV-2 results in approximately 1%-25% of cells becoming infected, suggesting a selective process. These data indicate that we are uniquely poised to test the hypothesis that ACE2 expressing cells constitute a unique reservoir of viral replication and are likely to mount an inflammatory cytokine response that is distinct from non-infected epithelia. Using our established team of experts in nasal epithelial cell biology, viral pathogenesis, inflammatory cytokine biology and genetics we will determine the following: A) which types of epithelia are virally infected, B) what are the local inflammatory cascades in infected vs. non-infected cells, and C) will pharmacologic manipulation of the epithelial innate defense pathways significantly alter SARS-CoV-2 ability to infect, replicate and be released from human nasal epithelia. Successful completion of this work is likely to have a major impact on development of novel strategies to combat COVID19 disease progression within the general population and especially in the U.S. Veteran population.", "keywords": [ "2019-nCoV", "ACE2", "Address", "Affect", "Age", "Air", "Anosmia", "Apical", "Asthma", "Basal Cell", "Biology", "Bronchitis", "COVID-19", "Caring", "Cell Lineage", "Cells", "Cellular biology", "Cessation of life", "Chronic Obstructive Pulmonary Disease", "Collaborations", "Communities", "Congestive", "Cryopreservation", "Data", "Detection", "Development", "Disease Progression", "Double-Stranded RNA", "Epithelial", "Epithelial Cells", "Functional disorder", "Future", "Gender", "General Population", "Genetic", "Genotype", "Goals", "Goblet Cells", "Growth", "Harvest", "Health", "Healthcare Systems", "Human", "Immune", "Immune response", "Immunologic Receptors", "Individual", "Infection", "Inflammatory", "Inflammatory Response Pathway", "Invaded", "Kinetics", "Knowledge", "Lead", "Light", "Liquid substance", "Malignant neoplasm of lung", "Medical", "Morbidity - disease rate", "Mucins", "Mucous Membrane", "Mucous body substance", "Nasal Epithelium", "Natural Immunity", "Nitric Oxide", "Nose", "Nucleocapsid Proteins", "Outcome", "Pathway interactions", "Patients", "Pennsylvania", "Peptide Hydrolases", "Pharmacology", "Predisposition", "Prevalence", "Prevention", "Process", "Production", "Prophylactic treatment", "Protocols documentation", "Pulmonary Emphysema", "RNA analysis", "Race", "Resources", "Respiration Disorders", "Respiratory Disease", "Respiratory Failure", "Respiratory Signs and Symptoms", "Respiratory Tract Infections", "Rhinitis", "Role", "SARS coronavirus", "SARS-CoV-2 infection", "Sampling", "Sinusitis", "Sputum", "Symptoms", "TMPRSS2 gene", "Testing", "Time", "Tissues", "Type 2 Angiotensin II Receptor", "Universities", "Veterans", "Viral", "Viral Genome", "Viral Pathogenesis", "Viral reservoir", "Virus", "Virus Diseases", "Virus Replication", "Virus Shedding", "Vulnerable Populations", "Work", "airway epithelium", "antimicrobial peptide", "asthma exacerbation", "biobank", "biosafety level 3 facility", "burden of illness", "combat", "comorbidity", "cytokine", "demographics", "discrete time", "experimental study", "high risk", "in vitro Model", "innate immune pathways", "insight", "military veteran", "mortality", "nasal swab", "novel strategies", "pandemic disease", "particle", "prophylactic", "racial disparity", "receptor", "screening", "single-cell RNA sequencing", "success", "targeted treatment", "transcriptome sequencing", "transmission process", "ultraviolet irradiation" ], "approved": true } }, { "type": "Grant", "id": "6779", "attributes": { "award_id": "5I01RX003666-02", "title": "Chronic Lung Disease and COVID-19: Understanding Severity, Recovery and Rehabilitation Needs (LAUREL Study)", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [], "program_reference_codes": [], "program_officials": [], "start_date": "2021-01-01", "end_date": "2024-12-31", "award_amount": null, "principal_investigator": { "id": 22583, "first_name": "Kristina Anne", "last_name": "Crothers", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1512, "ror": "", "name": "VA PUGET SOUND HEALTHCARE SYSTEM", "address": "", "city": "", "state": "WA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [ { "id": 22584, "first_name": "Aaron P.", "last_name": "Turner", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 1512, "ror": "", "name": "VA PUGET SOUND HEALTHCARE SYSTEM", "address": "", "city": "", "state": "WA", "zip": "", "country": "United States", "approved": true }, "abstract": "SARS-CoV-2 (SARS2) infection, which leads to COVID-19, is a global pandemic. Chronic lung disease (CLD), particularly chronic obstructive pulmonary disease (COPD), has emerged as a risk factor for infection and severity of COVID-19. Currently, very little is known of the long-term consequences of COVID-19 and how factors such as CLD, other comorbidities and social determinants of health (SDOH) influence the trajectory of recovery in survivors. While similar complications for COVID-19 survivors and risk factors for poor health recovery may be expected as in other causes of pneumonia and critical illness, long term outcomes of COVID- 19 have not been characterized or quantified. Patients who are hospitalized and critically ill are anticipated to have greater functional deficits, but even those with mild and moderate COVID-19 may have significant impacts on function given systemic involvement of infection; rehabilitation needs may be more likely to be under-recognized and unmet in many of these patients. Overall, functional outcomes may be worse than expected in all COVID-19 patients because of prolonged length of illness and barriers to receiving rehabilitation services, including restricted face-to-face interactions, limited capacity, and limited access for many. Because CLD is associated with increased frailty and impaired function, patients with CLD may be particularly vulnerable not only to infection but also sequalae of COVID-19. Given the current physical distancing environment, we urgently need a new paradigm for rehabilitation of patients recovering from COVID-19 that can inform and apply to other causes of pneumonia as well. In this proposal we will determine patient rehabilitation needs across the spectrum of severity of COVID-19, assessing if needs differ by CLD, comorbidity burden, SDOH or other patient risk factors. We will also assess the feasibility and acceptability of a novel, virtually-delivered, home-based personalized telerehabilitation program for survivors of COVID-19 that contains a COVID Reactivation and Engagement (CORE) intervention with exercise and dyspnea management and additional personalized modules based on patient needs. We will recruit patients treated for COVID-19 as outpatients or discharged directly home for this program. We have a multidisciplinary team with expertise in rehabilitation medicine, psychology, pulmonary, critical care, nursing, complementary and integrative health, quantitative and qualitative observational research and clinical trials, and will accomplish three separate aims: 1) Determine patient factors associated with severity and complications of COVID-19 utilizing VA EHR data; 2) Determine self-reported functional outcomes and trajectory of recovery after COVID- 19 in a prospective study using mixed methods; and 3) Examine the feasibility and acceptability of a virtually- delivered, home-based rehabilitation intervention for survivors of COVID-19, with components based on an individual patient’s needs. Results will characterize the recovery from COVID-19 and identify rehabilitation and care needs across domains of services that can be offered within VA. Our pilot study will inform larger trials to test the efficacy of this newly-developed program to improve functioning, reduce secondary symptoms, and improve quality of life among individuals recovering from COVID-19.", "keywords": [ "Acute", "Admission activity", "Anxiety", "COVID-19", "COVID-19 complications", "COVID-19 patient", "COVID-19 severity", "COVID-19 survivors", "COVID-19 treatment", "Cardiac", "Cardiovascular system", "Caregivers", "Caring", "Cessation of life", "Chronic", "Chronic Obstructive Pulmonary Disease", "Chronic lung disease", "Classification", "Clinical", "Clinical Trials", "Cognition", "Cognitive", "Complementary Health", "Coronavirus", "Critical Illness", "Data", "Dialysis procedure", "Disease", "Dyspnea", "Dyspnea Management", "Electronic Health Record", "Environment", "Event", "Exercise", "Future", "Health", "Healthcare Systems", "Home", "Hospitalization", "Hospitals", "Impairment", "Individual", "Infection", "Influenza", "Inpatients", "Integrative Medicine", "Intensive Care Units", "International", "Intervention", "Interview", "Location", "Lung", "Mental Depression", "Mental Health", "Methods", "Nurses", "Observational Study", "Outcome", "Outpatients", "Oxygen", "Pain", "Patient Recruitments", "Patient Self-Report", "Patient risk", "Patient-Focused Outcomes", "Patients", "Personal Satisfaction", "Physical Function", "Physical Medicine", "Pilot Projects", "Pneumonia", "Predisposition", "Prospective Studies", "Psychology", "Quality of life", "Recovery", "Rehabilitation therapy", "Reporting", "Risk", "Risk Factors", "SARS-CoV-2 infection", "Services", "Severities", "Stroke", "Surveys", "Survivors", "Symptoms", "Syndrome", "Time", "Veterans", "Veterans Health Administration", "acceptability and feasibility", "base", "community acquired pneumonia", "comorbidity", "coronavirus disease", "critical care nursing", "design", "disability", "efficacy testing", "feasibility testing", "follow-up", "frailty", "functional outcomes", "health administration", "health related quality of life", "hospital readmission", "illness length", "improved", "improved functioning", "individual patient", "infection risk", "long term consequences of COVID-19", "mortality", "multidisciplinary", "novel", "pandemic disease", "pilot test", "programs", "prospective", "rehabilitation paradigm", "rehabilitation service", "rehabilitative care", "satisfaction", "social health determinants", "telerehabilitation", "uptake", "virtual delivery" ], "approved": true } }, { "type": "Grant", "id": "6801", "attributes": { "award_id": "5I01BX005447-02", "title": "Immune mediated lung injury in COVID-19", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [], "program_reference_codes": [], "program_officials": [], "start_date": "2021-04-01", "end_date": "2023-03-31", "award_amount": null, "principal_investigator": { "id": 21877, "first_name": "Jane C", "last_name": "Deng", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 770, "ror": "", "name": "UNIVERSITY OF MICHIGAN AT ANN ARBOR", "address": "", "city": "", "state": "MI", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1477, "ror": "https://ror.org/05eq41471", "name": "Veterans Health Administration", "address": "", "city": "", "state": "MI", "zip": "", "country": "United States", "approved": true }, "abstract": "SARS-CoV-2 and the disease it causes (COVID-19) has emerged as a major global public health threat in the span of a few months. In particular, SARS-CoV-2 adds to the present number of acute respiratory infections, including influenza and bacterial pneumonia, which are endangering the health of our veterans and aging population. In particular, severe COVID-19 disease is characterized by severe lung injury, which results in severely impaired oxygen delivery and ultimately multiple organ failure and death. Our ongoing research has focused on a population of white blood cells called neutrophils, which are the most abundant white blood cell in our body and which have been shown to be a pivotal immune cell that contributes greatly to lung injury. However, our current medical knowledge is inadequate for understanding what neutrophils do in the context of viral infection. Although neutrophils are critical for eliminating many types of infections, they are believed to be a major contributor to the development of lung injury, and how to balance their beneficial activities with their harmful functions is poorly understood. Therefore, a better understanding of how neutrophils behavior and phenotype are altered during severe SARS-CoV-2 and other viral infections would aid in developing novel therapies to improve their antimicrobial functions, while limiting their injurious effects. The research we propose in this grant will examine how well neutrophils eliminate SARS-CoV-2 viruses, or if they are an excessively activated population of immune cells recruited to the lung whose harmful activities outweighs their benefits. We also will test an exciting new treatment approach developed by our collaborator at UCLA to see if this can block the damaging effects of neutrophils on lung cells, while blocking viral replication. The results of this 2-year project will provide insights into the beneficial versus harmful contributions of neutrophils in the development of severe COVID-19 disease, and potentially identify new therapies to benefit veterans and other vulnerable patients.", "keywords": [ "2019-nCoV", "Acute", "Acute Lung Injury", "Acute Respiratory Distress Syndrome", "Acute respiratory infection", "Age", "Animal Model", "Antiviral Agents", "Apoptosis", "Bacterial Pneumonia", "COVID-19", "COVID-19 pandemic", "Cardiopulmonary", "Cell Death", "Cells", "Cessation of life", "Chronic", "Coculture Techniques", "Collaborations", "Coronavirus", "Coronavirus Infections", "Data", "Development", "Disease", "Elderly", "Epithelial Cells", "Equilibrium", "Exposure to", "Failure", "Funding", "Grant", "Health", "Histones", "Host Defense", "Human", "Immune", "Immune response", "Immunology", "Immunotherapy", "Impairment", "In Vitro", "Infection", "Inflammation", "Inflammation Mediators", "Inflammatory Response", "International", "Knowledge", "Lead", "Leukocytes", "Literature", "Lung", "Lung infections", "Mechanical ventilation", "Mediating", "Mediator of activation protein", "Medical", "Modeling", "Morbidity - disease rate", "Mouse Strains", "Multiple Organ Failure", "Murine hepatitis virus", "Mus", "Natural Killer Cells", "Oxygen", "Pathogenesis", "Pathogenicity", "Pathology", "Patients", "Peptides", "Play", "Population", "Positioning Attribute", "Public Health", "Pulmonary Pathology", "Reporting", "Research", "Research Proposals", "Resolution", "Risk", "Risk Factors", "Role", "SARS-CoV-2 immunity", "SARS-CoV-2 infection", "Severe Acute Respiratory Syndrome", "Testing", "Veterans", "Viral", "Virus", "Virus Diseases", "Virus Replication", "Virus Shedding", "aging population", "antimicrobial", "antiviral immunity", "base", "behavioral phenotyping", "comorbidity", "cytotoxicity", "design", "extracellular", "fighting", "global health", "improved", "in vivo", "influenza pneumonia", "insight", "lung development", "lung injury", "male", "military veteran", "mortality", "neutrophil", "novel", "novel therapeutics", "pathogen", "patient population", "preservation", "prevent", "recruit", "repaired", "response", "severe COVID-19" ], "approved": true } }, { "type": "Grant", "id": "6810", "attributes": { "award_id": "5I01BX005434-02", "title": "COVID19: Optimized Endosome-Targeting Compounds for SARS-CoV-2 and Emerging Coronaviruses", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [], "program_reference_codes": [], "program_officials": [], "start_date": "2021-04-01", "end_date": "2023-03-31", "award_amount": null, "principal_investigator": { "id": 22628, "first_name": "Joseph Stone", "last_name": "Doggett", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1518, "ror": "https://ror.org/02v3txv81", "name": "Portland VA Medical Center", "address": "", "city": "", "state": "OR", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1518, "ror": "https://ror.org/02v3txv81", "name": "Portland VA Medical Center", "address": "", "city": "", "state": "OR", "zip": "", "country": "United States", "approved": true }, "abstract": "COVID-19 is a global health crisis that must be countered with the full capacity of government agencies, the private sector and the scientific community. New drugs that are broadly effective against coronaviruses are a crucial tool for ending this pandemic and preventing future coronavirus pandemics. Veterans are particularly at risk for severe COVID-19 due to older age and higher rates of cardiovascular disease. Initial efforts to repurpose drugs for COVID-19 have revived interest in the antiviral activity of the 4- aminoquinolines: chloroquine and hydroxychloroquine. Chloroquine has shown promise as an antiviral against many pathogenic viruses in past preclinical studies, but these results have not translated into clinical benefit. Initial clinical observations in China suggested that hydroxychloroquine may improve clinical outcomes, but as of yet, this evidence remains inconclusive. Overall, chloroquine’s broad antiviral activity indicates a promising antiviral mechanism that should be optimized by evaluating mechanistically similar compounds that target intracellular endosomes that are essential for viral pathogenesis. This research proposal will test a focused chemical library of 4-aminoquinolines and aminoacridones that are mechanistically similar to hydroxychloroquine against SARS-CoV-2 and related human coronaviruses. These compounds were designed to have less cardiac toxicity than chloroquine and enhanced accumulation in the Plasmodium digestive vacuole; properties that will likely lead to greater antiviral efficacy by creating higher drug concentrations in the intracellular endosomes that viruses require for host cell entry. Initial antiviral testing will both identify hits for preclinical evaluation and prioritization, and provide an extensive structure-activity- relationship to guide synthesis of new compounds with greater antiviral potency. The most potent compounds that are not toxic to human cells will be tested for target specificity, cardiac toxicity, and pharmacokinetic feasibility. The early lead compounds from these studies will be rapidly advanced to testing in animal models of SARS-CoV-2, other pathogenic coronaviruses and further preclinical testing via a separate funding mechanism. For the structure-activity-relationship, computational pharmacophore modeling will use the results of the initial antiviral testing, human cytotoxicity studies and target identification to identify structural features that enhance antiviral activity. Based on these models, new antiviral 4-aminoquinolines will be created and evaluated in the same manner as the hit compounds from the antiviral screen. This research will build on the repurposed compound, hydroxychloroquine, to quickly identify endosome targeting antivirals with greater clinical efficacy and safety for coronaviruses.", "keywords": [ "2019-nCoV", "4-aminoquinoline", "Age", "Animal Model", "Animals", "Antiviral Agents", "Biological Assay", "COVID-19", "COVID-19 pandemic", "COVID-19 treatment", "Cardiotoxicity", "Cardiovascular Diseases", "Cells", "China", "Chiroptera", "Chloroquine", "Clinical", "Clinical Trials", "Communities", "Coronavirus", "Dose", "Drug Kinetics", "Drug Screening", "Economics", "Endosomes", "Evaluation", "Funding Mechanisms", "Future", "Government Agencies", "Health", "Health protection", "Healthcare Systems", "Human", "Human Cell Line", "Hydroxychloroquine", "Image", "In Vitro", "Industry", "Infection", "Investigation", "Knowledge", "Lead", "Life", "Measures", "Metabolic", "Middle East Respiratory Syndrome", "Modeling", "Mus", "Oral", "Outcome", "Pathogenicity", "Pathway interactions", "Pharmaceutical Preparations", "Plasmodium", "Populations at Risk", "Preclinical Testing", "Prevalence", "Private Sector", "Property", "Prophylactic treatment", "Public Health", "Pulmonary Hypertension", "Reporting", "Research", "Research Proposals", "Risk", "SARS coronavirus", "SARS-CoV-2 inhibitor", "SARS-CoV-2 transmission", "Safety", "Science", "Severe Acute Respiratory Syndrome", "Specificity", "Structure-Activity Relationship", "Survival Analysis", "Symptoms", "Testing", "Toxic effect", "United States", "Vaccines", "Vacuole", "Vero Cells", "Veterans", "Viral Pathogenesis", "Virus", "Virus Replication", "Vulnerable Populations", "amphiphilicity", "anti-viral efficacy", "base", "clinical efficacy", "compound 30", "cytotoxicity", "design", "drug repurposing", "effective therapy", "global health", "human coronavirus", "human old age (65+)", "improved", "in vitro activity", "interest", "mortality", "novel coronavirus", "novel therapeutics", "pandemic disease", "pathogenic virus", "pharmacophore", "preclinical evaluation", "preclinical study", "prevent", "response", "severe COVID-19", "small molecule libraries", "tertiary amine", "tool", "transmission process", "warfighter", "zoonotic coronavirus" ], "approved": true } }, { "type": "Grant", "id": "6840", "attributes": { "award_id": "1IK2CX002192-01A2", "title": "Predictor Profiles of Opioid Use Disorders and Overdose Among Post-9/11 Veterans", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [], "program_reference_codes": [], "program_officials": [], "start_date": "2022-04-01", "end_date": "2027-03-31", "award_amount": null, "principal_investigator": { "id": 22670, "first_name": "Jennifer R", "last_name": "Fonda", "orcid": "https://orcid.org/0000-0001-9482-2918", "emails": "[email protected]", "private_emails": null, "keywords": "[]", "approved": true, "websites": "[]", "desired_collaboration": "", "comments": "", "affiliations": [ { "id": 1521, "ror": "", "name": "VA BOSTON HEALTH CARE SYSTEM", "address": "", "city": "", "state": "MA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1521, "ror": "", "name": "VA BOSTON HEALTH CARE SYSTEM", "address": "", "city": "", "state": "MA", "zip": "", "country": "United States", "approved": true }, "abstract": "The overall aim of this proposed study is to use machine learning prediction models to evaluate the multifaceted, additive and multiplicative interactions of known and novel risk factors for opioid use disorder (OUD) and overdose in Post-9/11 Veterans. The proposed study will also investigate the short- and long-term impact of the coronavirus disease 2019 (COVID-19) pandemic on the risk of OUD and overdose. TRAINING PLAN: The CDA-2 training plan will facilitate the applicant’s primary career goal of becoming a fully funded, independent epidemiologic researcher at the Department of Veterans Affairs (VA), with a focus on addiction and suicidal behavior. The CDA-2 will provide additional training necessary to lead an independent program of research investigating the multifaceted sociodemographic, physical, psychological, and behavioral factors mediating and moderating the risk of addiction and suicidal behavior. The first step of achieving this goal is to complete the following training aims: 1) gaining expertise in the biological and behavioral basis of addiction; 2) gaining expertise in the assessment of the problems of TBI and blast exposure, psychiatric disorders, and suicidal behavior, which is pervasive in this generation of Veterans; 3) gaining expertise in advanced analytic techniques employed in health data science, including machine learning algorithms; and 4) professional development to achieve career independence as a VA funded epidemiologic researcher. RESEARCH DESIGN & METHODS: The proposed study will use Veterans Health Administration (VHA) electronic medical records to develop models predicting OUD and overdose risk. The sample will include Post- 9/11 Veterans who are aged 18-65, receive care in the VHA, and will have completed the VA primary TBI screen between October 2007 and February 2020 (n~1,267,000). We will assess the risk of incident and recurrent OUD and overdose events, as separate outcomes, using machine learning algorithmic models. We will examine whether overdose was 1) fatal and non-fatal and 2) intentional and unintentional. For Aims 1 and 2, we will examine the risk of OUD and overdose events between October 1, 2007 and February 29, 2020. For Exploratory Aim 3, we will examine the risk of OUD and overdose events between March 1, 2020 and September 30, 2025. We will use several machine learning classification-tree modeling approaches, including classification and regression trees, random forest, and gradient boosting, to develop predictor profiles of OUD and overdose incorporating important risk factors and interactions. The validity (sensitivity and specificity) and prediction accuracy (area under the curve) will be assessed for all prediction profile models. OBJECTIVES: Aim 1: Develop and evaluate the performance of predictor profiles incorporating known and novel risk factors and interactions for OUD and overdose over proximal (30, 60, and 90 days) and distal (180, 365, 730, 1095 and >1460 days) prediction intervals using machine learning classification algorithms. Hypothesis 1a: The machine learning algorithms will have high validity and prediction accuracy (e.g., sensitivity and specificity and area under the curve) >0.8. Hypothesis 1b: Accuracy and predictive ability will be higher in the proximal vs. distal prediction intervals. Aim 2: Examine gender, race/ethnicity, deployment-related trauma (e.g., TBI and prevalent psychiatric and substance disorders), and close-blast exposure as moderators of the risk of OUD and overdose. Hypothesis 2: There will be novel risk factors and differential variable importance impacting the risk of OUD and overdose within the subgroup-specific predictor profiles. Exploratory Aim 3: Investigate the short- and long-term impact of the COVID-19 pandemic on the risk of OUD and overdose using machine learning classification algorithms to develop predictor profiles of known and novel risk factors and interactions. Hypothesis 3: The COVID-19 pandemic will have both a direct effect on the risk for OUD and overdose and an indirect effect through the onset or exacerbation of mental health symptoms and psychiatric conditions.", "keywords": [ "Adverse event", "Afghanistan", "Amalgam", "Anxiety", "Area Under Curve", "Behavioral", "Biological", "COVID-19 pandemic", "Caring", "Complex", "Computerized Medical Record", "Conflict (Psychology)", "Data", "Data Science", "Databases", "Development", "Disease", "Distal", "Domestic Violence", "Early Intervention", "Epidemiology", "Ethnic Origin", "Event", "Funding", "Gender", "General Population", "Generations", "Goals", "Health Services Accessibility", "High Prevalence", "Individual", "Intervention", "Iraq", "Lead", "Machine Learning", "Measures", "Mediating", "Mental Depression", "Mental Health", "Mental disorders", "Modeling", "Opioid", "Outcome", "Overdose", "Performance", "Population", "Post-Traumatic Stress Disorders", "Public Health", "Race", "Recording of previous events", "Recurrence", "Research", "Research Design", "Research Methodology", "Research Personnel", "Risk", "Risk Factors", "Sampling", "Sensitivity and Specificity", "Social Distance", "Subgroup", "Substance Use Disorder", "Symptoms", "Techniques", "Testing", "Training", "Trauma", "Traumatic Brain Injury", "United States", "United States Department of Veterans Affairs", "Veterans", "Veterans Health Administration", "Work", "addiction", "advanced analytics", "aged", "blast exposure", "career", "chronic pain", "classification algorithm", "classification trees", "cohort", "comorbidity", "disorder risk", "epidemiology study", "gradient boosting", "health data", "high risk", "improved", "machine learning algorithm", "machine learning classification", "machine learning method", "machine learning prediction", "military veteran", "novel", "opioid epidemic", "opioid misuse", "opioid use disorder", "overdose risk", "pandemic disease", "post 9/11", "precision medicine", "predictive modeling", "programs", "psychologic", "random forest", "regression trees", "sociodemographics", "study population", "suicidal behavior", "targeted treatment", "trauma exposure" ], "approved": true } }, { "type": "Grant", "id": "6841", "attributes": { "award_id": "1I01CX002322-01A1", "title": "Neural and cognitive consequences of COVID-19 survival.", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [], "program_reference_codes": [], "program_officials": [], "start_date": "2021-10-01", "end_date": "2025-09-30", "award_amount": null, "principal_investigator": { "id": 22671, "first_name": "Judith M", "last_name": "Ford", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1522, "ror": "", "name": "VETERANS AFFAIRS MED CTR SAN FRANCISCO", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [ { "id": 22672, "first_name": "Lynn", "last_name": "PULLIAM", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [] } ], "awardee_organization": { "id": 1522, "ror": "", "name": "VETERANS AFFAIRS MED CTR SAN FRANCISCO", "address": "", "city": "", "state": "CA", "zip": "", "country": "United States", "approved": true }, "abstract": "The SARS-CoV-2 pandemic has been going on for over a year worldwide, with 115,000,000 confirmed cases and over 2,500,000 deaths (as of Mar 3, 2021). We are seeing people recover from the initial COVID19 infection with complaints of ongoing problems. An increasing number of people are complaining of cognitive deficits and depression/anxiety. Veterans are at a higher risk of COVID19 infection as well as suffering complications due to a number of co-morbidities. Veterans with neurocognitive complications may experience premature aging and neurodegeneration that could manifest as a huge burden for health care. We have brought together two laboratories studying neurocognitive impairment using an EEG, MRI, and behavioral approach as well as laboratory-based data. The Ford lab proposes to query neuropsychological function in Veterans using a computerized internet-based neuropsychological battery, EEG-based measures, functional MRI (connectivity) and structural MRI (gray and white matter volumes, myelin, micro-bleeds). The Pulliam lab has preliminary data to show a continued increase in plasma cytokines in COVID19 survivors. Plasma isolated neuronal enriched extracellular vesicles (nEVs) showed an increase in amyloid beta, neurofilament light and pT181- Tau, all proteins associated with neurodegeneration. The Overall Aim is to determine the extent of the cognitive, clinical, and neurological damage in people recovered from COVID19. The Specific Aims are to: 1) characterize neuropsychological function in COVID19 survivors, 2) assess EEG and MRI data in COVID19 survivors, 3) determine whether peripheral inflammation and markers of neuroinflammation, aging, and neurodegeneration persist in nEVs, and 4) explore relationships between neurodegenerative and inflammatory blood markers and EEG/MRI/NP measures while considering pre-existing co-morbidities and complications of COVID19.", "keywords": [ "Age", "Aging", "Amyloid beta-Protein", "Anxiety", "Attention", "Auditory", "Behavioral", "Biological", "Biological Assay", "Biological Markers", "Blood", "Blood Vessels", "Brain", "Brain imaging", "COVID-19", "COVID-19 complications", "COVID-19 pandemic", "COVID-19 survivors", "Cells", "Cessation of life", "Clinic", "Clinical", "Cognition", "Cognitive", "Cognitive deficits", "Collaborations", "Data", "Diabetes Mellitus", "Electroencephalography", "Event", "Event-Related Potentials", "Functional Magnetic Resonance Imaging", "Functional disorder", "HIV", "Healthcare", "Impaired cognition", "Infection", "Inflammatory", "Internet", "Laboratories", "Laboratory Study", "Light", "Lung", "Magnetic Resonance Imaging", "Measures", "Memory", "Mental Depression", "Methods", "Myelin", "Nerve Degeneration", "Nervous System Trauma", "Neural Cell Adhesion Molecule L1", "Neurocognitive", "Neurocognitive Deficit", "Neurologic", "Neuronal Dysfunction", "Neurons", "Neurophysiology - biologic function", "Neuropsychology", "Obesity", "P300 Event-Related Potentials", "Parents", "Pathologic", "Patient Recruitments", "Peripheral", "Persons", "Pilot Projects", "Plasma", "Precipitation", "Premature aging syndrome", "Proteins", "Psychological Tests", "Reporting", "Rest", "SARS-CoV-2 infection", "SARS-CoV-2 positive", "San Francisco", "Signal Transduction", "Smoking", "Techniques", "Time", "Translating", "Veterans", "Work", "base", "body system", "cell injury", "cognitive function", "comorbidity", "computerized", "coronavirus disease", "cytokine", "experience", "experimental study", "extracellular vesicles", "gray matter", "high risk", "inflammatory marker", "long-term sequelae", "magnetic resonance imaging/electroencephalography", "neurofilament", "neuroimaging", "neuroinflammation", "neurophysiology", "novel coronavirus", "post-COVID-19", "relating to nervous system", "response", "tau Proteins", "white matter" ], "approved": true } }, { "type": "Grant", "id": "6860", "attributes": { "award_id": "5I01BX001352-10", "title": "Endothelial topography, phosphatidylserine, and procoagulant activity", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [], "program_reference_codes": [], "program_officials": [], "start_date": "2012-01-01", "end_date": "2025-03-31", "award_amount": null, "principal_investigator": { "id": 22695, "first_name": "Gary E", "last_name": "Gilbert", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1521, "ror": "", "name": "VA BOSTON HEALTH CARE SYSTEM", "address": "", "city": "", "state": "MA", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1521, "ror": "", "name": "VA BOSTON HEALTH CARE SYSTEM", "address": "", "city": "", "state": "MA", "zip": "", "country": "United States", "approved": true }, "abstract": "Blood coagulation enzymes function efficiently only on membranes containing phosphatidylserine. However, phosphatidylserine is not ordinarily available because blood cells sequester it on the interior of cell membranes. Blood platelets respond to collagen in injured tissue, exposing abundant phosphatidylserine on bleb-like protrusions of the membrane and these platelets have been called “procoagulant platelets” and are thought to be essential for prevention of bleeding. However, recent clinical information from patients with platelet phosphatidylserine-exposing defects indicate that these patients have only mild-moderate bleeding from mucous membranes. This raises the question as to whether platelet phosphatidylserine exposure is, indeed, a critical component of blood coagulation. Preliminary studies from our laboratory have identified several factors that may help to explain the apparent contradiction. First, blood coagulation complexes recognize convex membrane curvature in addition to phosphatidylserine content. A membrane with protrusions and invaginations may have coagulation complexes highly localized to the convex protrusions. Second, platelets and endothelial cells have modes of limited membrane phosphatidylserine exposure. In these modes, phosphatidylserine exposure is below the threshold of detection for most phosphatidylserine assays. Thus, low level phosphatidylserine exposure is present and can support coagulation complexes, yet goes undetected. Third, phosphatidylserine-rich membranes also support anticoagulant proteins to a degree that can suppress or eliminate the procoagulant potential. The net anticoagulant effect, like procoagulant support, is dependent on both phosphatidylserine content and on membrane curvature. These insights, and the methods used to gain them, give us the unique opportunity to study the manner in which platelet and endothelial cell phosphatidylserine exposure localizes procoagulant enzyme activity. We have hypothesized that blood anticoagulants ordinarily suppress the procoagulant potential of stimulated platelets with phosphatidylserine-rich blebs. The platelets gain true procoagulant activity in environments where anticoagulants are attenuated or bypassed by proteins in the micro-environment. This proposal will focus on gaining insight into the anticoagulant proteins that ordinarily suppress blood coagulation reactions on procoagulant complexes, particularly in regard to phosphatidylserine exposure and membrane curvature. We will next probe the extent to which the anticoagulants effect is attenuated or bypassed by the effects of plasmin in the context of mucous membranes. In addition, we will study the manner in which conditioned endothelial support limited blood coagulation reactions on focal, highly complex membrane projections. We will also evaluate the extent to which the endothelial procoagulant activity may be amplified by adherent platelets and whether the endothelial generated factor Xa bypasses anticoagulant activity on platelet blebs. The platelet studies will provide insights relevant to treating surgical and traumatic bleeding, relevant to hemostasis for hemophilia patients. The endothelial studies are relevant to the coagulopathy known as disseminated intravascular coagulation and relevant to the vascular injury and inflammation of COVID-19.", "keywords": [ "Anticoagulants", "Anticoagulation", "Attenuated", "Binding", "Biological Assay", "Biophysics", "Blood", "Blood Cells", "Blood Coagulation Disorders", "Blood Platelets", "Blood Vessels", "Blood coagulation", "Bulla", "Bypass", "COVID-19", "Cell membrane", "Cells", "Cellular biology", "Childbirth", "Clinical", "Coagulation Process", "Collagen", "Complex", "Confocal Microscopy", "Defect", "Detection", "Disseminated Intravascular Coagulation", "Endothelial Cells", "Endothelium", "Engineering", "Environment", "Enzymes", "Evaluation", "Factor V", "Factor VIIa", "Factor XIa", "Factor Xa", "Filopodia", "Flow Cytometry", "Hemophilia A", "Hemorrhage", "Hemostatic Agents", "Hemostatic function", "Human", "Impairment", "In Vitro", "Individual", "Inflammation", "Knowledge", "Laboratories", "Location", "Measures", "Mediating", "Membrane", "Methodology", "Methods", "Microfluidics", "Modeling", "Mucous Membrane", "Multienzyme Complexes", "Mus", "Operative Surgical Procedures", "Pathology", "Pathway interactions", "Patients", "Peptide Hydrolases", "Phosphatidylserines", "Phospholipids", "Plasma", "Plasmin", "Pore Proteins", "Prevention", "Protein S", "Proteins", "Reaction", "Regulation", "Scott syndrome", "Spatial Distribution", "Stress", "Surgical Hemostasis", "TFPI", "Tail", "Testing", "Therapeutic", "Thrombin", "Thromboplastin", "Time", "Tissues", "Trauma", "Umbilical vein", "Vesicle", "Work", "activated Protein C", "attenuation", "cofactor", "enzyme activity", "experience", "genetic regulatory protein", "inhibitor/antagonist", "injured", "innovation", "insight", "novel", "response", "vascular inflammation", "vascular injury" ], "approved": true } }, { "type": "Grant", "id": "6912", "attributes": { "award_id": "1IK2RX003546-01A2", "title": "Enhanced Home-Based Exercise Therapy for Peripheral Arterial Disease through Mobile Health and Remote Monitoring", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [], "program_reference_codes": [], "program_officials": [], "start_date": "2021-10-01", "end_date": "2026-09-30", "award_amount": null, "principal_investigator": { "id": 22750, "first_name": "Arash", "last_name": "Harzand", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1477, "ror": "https://ror.org/05eq41471", "name": "Veterans Health Administration", "address": "", "city": "", "state": "MI", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1477, "ror": "https://ror.org/05eq41471", "name": "Veterans Health Administration", "address": "", "city": "", "state": "MI", "zip": "", "country": "United States", "approved": true }, "abstract": "An estimated 8.5 million Americans (or 7% of US adults) and nearly 10% of veterans are estimated to have peripheral arterial disease (PAD). Significantly debilitating and negatively impacting quality of life, the primary symptom of PAD is claudication (reproducible leg pain with ambulation) that leads to impaired mobility, loss of functional independence, and a heightened risk for amputation. Veterans are at an increased risk of developing symptomatic PAD due to their disproportionately high rates of PAD risk factors such as diabetes, smoking, and hypertension, the most prominent PAD risk factors. Supervised exercise therapy is proven to decrease claudication and enhance mobility in PAD; however, fewer than 25% of eligible patients enroll. Participation in this facility-based program requires travel to a rehabilitation center 3 times per week for 12-weeks, which can be burdensome and costly for Veterans, many of whom live in rural areas and on fixed incomes. There is, therefore, a need to develop a convenient and effective alternative exercise rehabilitation program for Veterans with PAD, particularly in light of safety considerations now associated with this population’s travel to group facilities in the current COVID pandemic. A promising approach to increase access to exercise rehabilitation for PAD is remote, home-based exercise therapy (HBET). Our group has successfully delivered a smartphone-enabled HBET program to Veterans with coronary artery disease with a 3-fold increase in participation and high satisfaction (80%). To this end, we are committed to utilizing technology innovations to implement HBET for Veterans with PAD successfully. HBET programs combine self-led walking exercises with health coaching and exercise tracking with a wearable activity monitor. Adapting HBET to PAD is difficult, however, due to the added complexity of an exercise prescription that requires the patient to walk until they experience near-maximal leg pain. Even with active coaching, successfully implementing HBET for PAD with long-term adherence has been difficult in the past. Our goal, therefore, is to leverage newer mobile health (mHealth) tools to adapt HBET for PAD. We propose to test our technology-enhanced approach for HBET by partnering with a successful VA lifestyle program, MOVE!, which has demonstrated success in achieving sustained weight loss and reduced diabetes onset through lifestyle modification. As increased physical activity is a core element of MOVE!, participation may help increase adherence with HBET for PAD. Our newly proposed program, Smart MOVE!, will be a multi-component program featuring a tailored version of MOVE! and a novel mHealth device called the LifeQ to improve convenience, access, and adherence to HBET for PAD. Aim 1 (Years 1-2): Identify barriers and facilitators to MOVE! participation among Veterans with PAD. Aim 2 (Years 1-2): Evaluate the feasibility of the LifeQ device to monitor exercise during HBET Aim 3 (Years 2-5): Determine the feasibility of proceeding with Smart MOVE! through a pilot randomized trial. As a VA physician actively treating Veterans with PAD, I have seen first-hand the challenges they face in accessing guideline-directed treatments such as supervised exercise. This study will lay the groundwork and provide evidence to proceed with Smart MOVE!, a much-needed patient-centered exercise rehabilitation program for PAD. Additionally, the proposed training plan will support my progress towards becoming an independent VA rehabilitation clinician-scientist focused on improving care quality and treatment outcomes for Veterans with PAD.", "keywords": [ "Accelerometer", "Activities of Daily Living", "Adherence", "Adult", "Affect", "American", "Amputation", "Behavioral", "Body Weight decreased", "COVID-19 pandemic", "Cardiac rehabilitation", "Cellular Phone", "Clinical", "Complex", "Coronary Arteriosclerosis", "Data", "Devices", "Diabetes Mellitus", "Elements", "Enhancement Technology", "Enrollment", "Exercise", "Exercise Therapy", "Face", "Goals", "Gold", "Guidelines", "Health", "Health Technology", "Home", "Hospitals", "Hypertension", "Impairment", "Income", "Indirect Calorimetry", "Intervention", "Interview", "Leadership", "Leg", "Life Style", "Life Style Modification", "Light", "Measurement", "Monitor", "Myocardial Infarction", "Oxygen Consumption", "Pain in lower limb", "Patient Education", "Patients", "Peripheral arterial disease", "Physical activity", "Physicians", "Population", "Provider", "Quality of Care", "Quality of life", "Rehabilitation Centers", "Rehabilitation therapy", "Reproducibility", "Resolution", "Risk", "Risk Factors", "Safety", "Scientist", "Smoking", "Stroke", "Structure", "Supervision", "Symptoms", "Technology", "Testing", "Time", "Training", "Travel", "Treatment outcome", "Vertebral column", "Veterans", "Walking", "aged", "base", "behavior change", "claudication", "cost", "design", "evidence base", "exercise prescription", "exercise program", "exercise regimen", "exercise rehabilitation", "experience", "functional independence", "functional loss", "functional outcomes", "high risk", "improved", "improved mobility", "informant", "innovation", "mHealth", "mortality risk", "multi-component intervention", "novel", "patient oriented", "primary outcome", "programs", "randomized trial", "remote monitoring", "rural area", "satisfaction", "success", "symptomatic improvement", "tool" ], "approved": true } }, { "type": "Grant", "id": "6913", "attributes": { "award_id": "2I01BX004270-04A1", "title": "Development of Novel Second Generation Anti-inflammatory Substrate-selective p38 MAP Kinase Inhibitors as Therapy for Acute Respiratory Distress Syndrome", "funder": { "id": 4, "ror": "https://ror.org/01cwqze88", "name": "National Institutes of Health", "approved": true }, "funder_divisions": [], "program_reference_codes": [], "program_officials": [], "start_date": "2018-07-01", "end_date": "2025-12-31", "award_amount": null, "principal_investigator": { "id": 22751, "first_name": "JEFFREY D", "last_name": "HASDAY", "orcid": null, "emails": "", "private_emails": "", "keywords": null, "approved": true, "websites": null, "desired_collaboration": null, "comments": null, "affiliations": [ { "id": 1532, "ror": "https://ror.org/036a0e562", "name": "Baltimore VA Medical Center", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true } ] }, "other_investigators": [], "awardee_organization": { "id": 1532, "ror": "https://ror.org/036a0e562", "name": "Baltimore VA Medical Center", "address": "", "city": "", "state": "MD", "zip": "", "country": "United States", "approved": true }, "abstract": "Acute Respiratory Distress Syndrome (ARDS) affects ~190,000 patients and causes ~75,000 deaths per year in the U.S.A. ARDS has a mortality rate of ~40% and causes significant morbidity in survivors. Respiratory viruses, including influenza and now Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), are important causes of ARDS with limited therapeutic options. The VA patient population has many of the risk factors for having poor outcomes with ARDS, including older age, obesity, hypertension, diabetes, and chronic lung and heart disease. There are no currently available pharmacologic therapies proven to be effective in ARDS. To address this need, we developed a novel class of substrate- and function-selective p38 mitogen- activated protein kinases (MAPK) inhibitors with anti-inflammatory and endothelial-barrier stabilizing activity. Compared with conventional p38 catalytic inhibitors that block all downstream signaling including anti- inflammatory pathways, our novel compounds target one of the substrate docking sites and therefore only block certain p38-dependent processes. Together with my co-investigators, Drs. Shapiro, MacKerell, and Fletcher, we used computer-aided drug design (CADD) to identify a lead compound, UM101, that binds a pocket near the ED substrate docking site on p38a and exhibits a unique profile of biological activities. We developed a second-generation analog, SF7044, with greater solubility and improved endothelial barrier- stabilizing, anti-inflammatory, and lung-protective activities. We are currently collaborating with Gen1e Life Sciences, LLC, which licensed the patents for these compounds, completed preclinical testing and began clinical testing of SF7044. During our current Merit Award, we identified and screened 200 additional compounds targeted to the same substrate docking site as UM101 using a refined CADD strategy. We identified four new lead compounds with superior endothelial barrier stabilizing activity and p38a-binding compared with UM101 and SF7044 and distinct anti-inflammatory effect profiles, but poor solubility. In vivo testing in a mouse model will require reformulation or chemical modification of these new lead compounds to improve solubility (like UM101). The overall objective of this renewal is to use the same strategy as used for development of SF7044 to design, synthesize, and characterize second-generation analogs of the four new lead compounds with improved activity and drug-like properties. Since the new lead compounds have greater endothelial-stabilizing activity and p38a-binding than either UM101 or SF7044 we expect to develop second- generation analogs with substantially improved lung-protective activity. We will utilize CADD and medicinal chemistry principles, protein binding assays and human cell and mouse models of ALI: 1. Design and synthesize at least 20 analogs of each the 4 newly discovered lead compounds to improve p38a-binding and drug-like properties. 2. Analyze the second-generation analogs for target binding and biological activities. 3. Analyze toxicity and effectiveness of the most active second-generation analogs in mouse models of the exudative (LPS/hyperthermia) and fibroproliferative (bleomycin) phases of ARDS. 4. Evaluate new compounds for off-target effects At the conclusion of this work, we will have developed second generation analogs of novel non-catalytic p38α inhibitors with improved efficacy and safety profiles in mouse lung injury models to provide a pipeline of new compounds that are ready for advanced preclinical testing prior to clinical testing in ARDS.", "keywords": [ "2019-nCoV", "Acute Lung Injury", "Acute Respiratory Distress Syndrome", "Address", "Affect", "Affinity", "Age", "Anti-Inflammatory Agents", "Antiinflammatory Effect", "Aspartate", "Award", "Binding", "Binding Proteins", "Biological", "Biological Assay", "Biological Sciences", "Bleomycin", "Blood Vessels", "COVID-19", "COVID-19/ARDS", "Catalytic Domain", "Cell model", "Cells", "Cessation of life", "Chemicals", "Chronic lung disease", "Clinic", "Clinical Trials", "Complication", "Computer Assisted", "Computers", "Databases", "Death Rate", "Development", "Diabetes Mellitus", "Docking", "Dose", "Drug Design", "Drug Kinetics", "Effectiveness", "Endothelium", "Exhibits", "Fever", "Funding", "Future", "Generations", "Glutamates", "Goals", "Heart Diseases", "Human", "Hypertension", "Hyperthermia", "In Vitro", "Infection", "Inflammation", "Influenza", "Injury", "Lead", "Legal patent", "Lung", "Maps", "Maryland", "Mitogen-Activated Protein Kinase Inhibitor", "Mitogen-Activated Protein Kinases", "Mitogens", "Modeling", "Modification", "Molecular", "Monkeys", "Morbidity - disease rate", "Mus", "Obesity", "Outcome", "Pathogenicity", "Pathway interactions", "Patients", "Permeability", "Pharmaceutical Chemistry", "Pharmaceutical Preparations", "Pharmacodynamics", "Pharmacology", "Pharmacy Schools", "Phase", "Phosphotransferases", "Plasma", "Preclinical Testing", "Preparation", "Process", "Program Development", "Property", "Protective Agents", "Protein Kinase", "Protein phosphatase", "RPS6KA5 gene", "Rattus", "Research Personnel", "Risk Factors", "Safety", "Services", "Signal Transduction", "Site", "Solubility", "Specificity", "Surface Plasmon Resonance", "Survivors", "Testing", "Therapeutic", "Thrombin", "Toxic effect", "Universities", "Veterans", "Virus", "Work", "analog", "aqueous", "cytokine", "design", "disability", "drug candidate", "drug development", "efficacy testing", "epithelial injury", "improved", "in vivo", "in vivo evaluation", "inhibitor/antagonist", "kinase inhibitor", "lung injury", "mortality", "mouse model", "multimodality", "novel", "novel therapeutics", "p38 Mitogen Activated Protein Kinase", "patient population", "protective effect", "pulmonary artery endothelial cell", "receptor", "receptor binding", "research clinical testing", "respiratory virus", "safety study", "scaffold", "screening", "stress activated protein kinase", "therapeutic candidate", "therapeutic target" ], "approved": true } } ], "meta": { "pagination": { "page": 1383, "pages": 1397, "count": 13961 } } }