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

• 批准号: 10390483
• 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
• 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/10390483
• 关键词: Academic Medical Centers; Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Adult; 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; Strategic vision; 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; 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

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.

项目摘要 急性呼吸窘迫综合征（ARDS）在美国每年影响超过20万成年人 有很高的死亡风险。易感性和结局的异质性是 对ARDS的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：确定的关键挑战 在NHLBI最新的战略愿景计划中。本K 01提案将提供V. Eric Kerchberger博士（医学博士） 他的长期职业目标是通过应用他的专业知识， 生物医学信息学和遗传分析方面的专业知识，以利用大规模电子健康的力量 记录（EHR）数据库和DNA生物库。该项目将在小学的指导下完成 洛琳导师B。Ware，MD和共同导师Wei-Qi Wei，MD，PhD，以及一个研究咨询委员会， 精准医学、生物医学信息学和功能基因组学专家。通过整合现有的GWAS- 水平基因分型与PrediXcan，一个先进的功能基因组学框架，该项目将量化组织- 3,100名重症成年人的肺组织和免疫细胞的特定基因表达水平， 急性肺损伤诊断标志物（VALID）研究队列验证。然后，利用Kerchberger博士的 在EHR表型方面的专业知识，我们将在一个独立的样本中验证VALID的遗传发现， 来自BioVU，范德比尔特大学医学中心大型去识别DNA生物库的ARDS患者。这 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， 基因表达与成人急性呼吸窘迫综合征易感性目的2：检测基因之间的关联 基因表达调控和以患者为中心的结果在ARDS。目标3：使用高级表型分析 在BioVU中识别ARDS患者和高危对照的方法，并复制基因表达相关性 确认为有效。 这些研究的完成将产生新的方法，以确定ARDS患者和风险控制，从大的 EHR数据库，并推进我们对ARDS组织特异性基因表达的理解，弥合差距 遗传学和生物学之间的联系从这一建议中获得的知识将为以下方面提供重要的初步数据： 博士Kerchberger将设计和执行未来的R 01提案，使用NIH研究ARDS的功能基因组学- 支持EHR生物库，如电子医疗记录和基因组学网络和NIH 美国项目。此外，Kerchberger博士将获得功能基因组学临床翻译的新技能 和先进的EHR表型，为Kerchberger博士独立领导奠定了基础。 由临床医生、遗传学家和数据科学家组成的协作团队，进行基于EHR的大型关键研究， 疾病综合征将改善风险预测，利用遗传风险识别新的疾病亚型， 最终为重症患者带来精准医疗。