Tissue-specific functional genomics in the acute respiratory distress syndrome

项目总结 急性呼吸窘迫综合征(ARDS)每年影响美国20多万成年人 而且有很高的死亡率。易感性和结果的异质性是该病的显著特征 ARDS，以及对ARDS遗传基础的更好理解将提高我们定义 ARDS亚型、预测疾病风险和确定新的治疗靶点：已确定的关键挑战 在NHLBI最新的战略愿景计划中。这份K01提案将为医学博士V.Eric Kerchberger提供 接受了关键培训，为他的长期职业目标--通过应用他的 在生物医学信息学和基因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 导师Lorraine B.Ware，医学博士和共同导师魏伟-齐威，医学博士，以及 精准医学、生物医学信息学和功能基因组学方面的专家。通过整合现有的全球气候变化网络-- 使用PrediXcan，一个先进的功能基因组学框架，这个项目将量化组织- 3100名危重成人肺组织和免疫细胞的特异性基因表达水平 验证急性肺损伤标志物用于诊断(有效)的研究队列。然后，利用克奇伯格博士的 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有效的遗传发现 来自BioVU的ARDS患者，范德比尔特大学医学中心的大型去识别DNA生物库。这 指导研究项目有三个具体目标：目标1：测试基因调控与 高危成人的基因表达与ARDS易感性。目标2：测试基因和基因之间的关联 ARDS中基因表达的调节和以患者为中心的结果。目标3：使用高级表型分析 方法在BioVU中识别ARDS患者和高危对照，并复制基因表达关联 确认为有效。 这些研究的完成将产生新的方法来识别ARDS患者和高危对照 EHR数据库，并促进我们对ARDS组织特异性基因表达的理解，弥补了这一差距 在遗传学和生物学之间。从这项提案中获得的知识将为以下工作提供重要的初步数据 Kerchberger博士将设计和执行未来的R01提案，利用NIH--研究ARDS的功能基因组学 支持的EHR生物库，如电子病历和基因组学网络和NIH 美国项目。此外，Kerchberger博士将在功能基因组学的临床翻译方面获得新的技能 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的大型关键疾病研究 疾病症状将改进风险预测，利用遗传风险识别新的疾病亚型，以及 最终为危重病人带来精准医疗。

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.