Tissue-specific functional genomics in the acute respiratory distress syndrome

急性呼吸窘迫综合征的组织特异性功能基因组学

基本信息

批准号：
10191767
负责人：
Vern Eric Kerchberger
金额：
$ 16.88万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10191767
关键词：
Academic Medical Centers Acute Acute Lung Injury Address Adult Adult Respiratory Distress Syndrome Advisory Committees Affect Biology Biopsy Cells Chronic Disease Clinical Cohort Studies Computerized Medical Record Critical Care Critical Illness DNA Data Data Scientist Databases Diagnosis Disease Disease Outcome Disease susceptibility Doctor of Philosophy Electronic Health Record Electronic Medical Records and Genomics Network Enrollment Foundations Future Gene Expression Gene Expression Regulation Genes Genetic Genetic Predisposition to Disease Genetic Risk Genetic study Genomics Genotype Goals Healthcare Systems Heterogeneity Immune Individual Inflammation Investigation Knowledge Lead Lung Lymphocyte Measures Mentors Mentorship Methods Modeling National Heart, Lung, and Blood Institute Outcome Pathogenesis Patient-Focused Outcomes Patients Performance Phenotype Predisposition Qi Research Research Personnel Research Project Grants Resources Risk Sampling Single Nucleotide Polymorphism Source Structure Structure of parenchyma of lung Syndrome Testing Tissue Sample Tissue-Specific Gene Expression Tissues Training United States United States National Institutes of Health Variant Vision Whole Blood base biobank biomedical informatics career cell type classifier algorithm clinical translation cohort computer framework design differential expression disorder risk disorder subtype functional genomics gene function genetic analysis genetic information genetic variant genome wide association study high risk human tissue improved innovation mortality risk new therapeutic target novel patient oriented personalized care population based precision medicine prospective risk prediction skills transcriptome

项目摘要

PROJECT SUMMARY The acute respiratory distress syndrome (ARDS) affects more than 200,000 adults each year in the United States and carries a high mortality risk. Heterogeneity in susceptibility and outcomes are prominent features of ARDS, and improved understanding of the genetic underpinnings of ARDS would advance our ability to define ARDS subphenotypes, predict disease risk, and identify new therapeutic targets: a critical challenge identified in the NHLBI’s most recent Strategic Vision plan. This K01 proposal will provide Dr. V. Eric Kerchberger, MD with critical training for his long-term career goal of bringing precision medicine to critical care by applying his expertise in biomedical informatics and genetic analysis to leverage the power of large-scale electronic health record (EHR) databases and DNA biobanks. The project will be completed under the guidance of primary mentor Lorraine B. Ware, MD and co-mentor Wei-Qi Wei, MD, PhD, and a research advisory committee of experts in precision medicine, biomedical informatics, and functional genomics. By integrating existing GWAS- level genotyping with PrediXcan, an advanced functional genomics framework, this project will quantify tissue- specific gene expression levels for lung tissue and immune cells in 3,100 critically ill adults enrolled in the Validating Acute Lung Injury Markers for Diagnosis (VALID) Study cohort. Then, leveraging Dr. Kerchberger’s expertise in EHR phenotyping, we will validate the genetic findings from VALID in an independent sample of ARDS patients from BioVU, Vanderbilt University Medical Center’s large de-identified DNA biobank. This mentored research project has three specific aims: Aim 1: Test the association between genetic regulation of gene expression and ARDS susceptibility in at-risk adults. Aim 2: Test the association between genetic regulation of gene expression and patient-centered outcomes in ARDS. Aim 3: Use advanced phenotyping methods to identify ARDS patients and at-risk controls in BioVU, and replicate gene expression associations identified in VALID. Completion of these studies will yield novel methods to identify ARDS patients and at-risk controls from large EHR databases, and advance our understanding of tissue-specific gene expression in ARDS, bridging the gap between genetics and biology. The knowledge gained from this proposal will provide vital preliminary data for Dr. Kerchberger to design and execute future R01 proposals to study functional genomics in ARDS using NIH- supported EHR biobanks such as the Electronic Medical Records and Genomics Network and the NIH All of Us Project. Furthermore, Dr. Kerchberger will gain new skills in the clinical translation of functional genomics and advanced EHR phenotyping, forming the foundation for Dr. Kerchberger to independently lead collaborative teams of clinicians, geneticists, and data scientists to conduct large EHR-based studies of critical illness syndromes that will improve risk prediction, identify novel disease subtypes using genetic risk, and ultimately bring precision medicine to the critically ill patient.

项目概要在美国，急性呼吸窘迫综合征 (ARDS) 每年影响超过 200,000 名成年人易感性和结果的异质性是其显着特征。 ARDS 以及对 ARDS 遗传基础的进一步了解将提高我们定义 ARDS 的能力 ARDS 亚表型、预测疾病风险并确定新的治疗靶点：已确定的关键挑战 NHLBI 最新的战略愿景计划中的 K01 提案将提供 V. Eric Kerchberger 博士（医学博士）。为他的长期职业目标提供了关键的培训，即通过应用他的技术将精准医学带入重症监护生物医学信息学和遗传分析方面的专业知识，以利用大规模电子医疗的力量记录（EHR）数据库和DNA生物库该项目将在主要指导下完成。导师 Lorraine B. Ware（医学博士）和联合导师 Wei-Qi Wei（医学博士、博士）以及研究咨询委员会精准医学、生物医学信息学和功能基因组学领域的专家通过整合现有的 GWAS- 使用 PrediXcan（一种先进的功能基因组学框架）进行水平基因分型，该项目将量化组织- 参与该研究的 3,100 名危重成人的肺组织和免疫细胞的特定基因表达水平然后，利用 Kerchberger 博士的研究队列验证急性肺损伤标志物的诊断（VALID）。凭借 EHR 表型分析方面的专业知识，我们将在独立样本中验证 VALID 的基因发现来自范德比尔特大学医学中心大型去识别 DNA 生物库 BioVU 的 ARDS 患者。指导研究项目有三个具体目标：目标 1：测试基因调控之间的关联高危成人的基因表达和 ARDS 易感性目标 2：测试遗传之间的关联。 ARDS 中基因表达的调控和以患者为中心的结果。目标 3：使用先进的表型分析。在 BioVU 中识别 ARDS 患者和高危对照并复制基因表达关联的方法已识别为有效。这些研究的完成将产生新的方法来识别大型 ARDS 患者和高危对照。 EHR 数据库，增进我们对 ARDS 组织特异性基因表达的理解，弥合差距从该提案中获得的知识将为遗传学和生物学之间的研究提供重要的初步数据。 Kerchberger 博士将设计并执行未来的 R01 提案，利用 NIH- 研究 ARDS 的功能基因组学支持 EHR 生物库，例如电子病历和基因组网络以及 NIH 所有此外，Kerchberger 博士还将获得功能基因组学临床转化方面的新技能。和先进的 EHR 表型分析，为 Kerchberger 博士独立领导奠定了基础由反叛者、遗传学家和数据科学家组成的协作团队对关键问题进行基于电子病历的大型研究疾病综合症将改善风险预测，利用遗传风险识别新的疾病亚型，以及最终为危重患者带来精准医疗。