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：
10610722
负责人：
Vern Eric Kerchberger
金额：
$ 16.91万
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/10610722
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 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 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 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.

项目摘要急性呼吸窘迫综合征（ARDS）每年在统一影响200,000多名成年人国家和具有高死亡率风险。敏感性和结果的异质性是 ARDS以及对ARDS遗传基础的理解的提高将提高我们定义的能力 ARDS亚表现型，预测疾病风险并确定新的治疗靶标：确定的关键挑战在NHLBI的最新战略愿景计划中。该K01提案将为MD的V. Eric Kerchberger博士提供通过对他的长期职业目标进行关键培训，将精密医学带到重症监护生物医学信息和遗传分析方面的专业知识，以利用大规模电子健康的能力记录（EHR）数据库和DNA生物库。该项目将在主要的指导下完成导师Lorraine B. Ware，医学博士和Co-entor Wei-Qi Wei，医学博士，博士和研究咨询委员会精密医学，生物医学信息和功能基因组学专家。通过整合现有的gwas- Predixcan的水平基因分型是一种高级功能基因组学框架，该项目将量化组织 - 在3,100名危重患病的成年人中，肺组织和免疫细胞的特定基因表达水平验证诊断急性肺损伤标记（有效）研究队列。然后，利用Kerchberger博士的在EHR表型方面的专业知识，我们将在独立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DNA生物库。这 Menored Research项目具有三个具体目标：目标1：测试遗传调节的关联高危成年人中的基因表达和敏感性。目标2：测试通用之间的关联调节基因表达和以患者为中心的ARDS的调节。目标3：使用高级表型识别BIOVU中ARDS患者和高风险对照的方法，并复制基因表达关联在有效中确定。这些研究的完成将产生新的方法来鉴定大型ARDS患者和高危对照 EHR数据库，并促进我们对ARDS中组织特异性基因表达的理解，弥合差距在遗传学和生物学之间。从该提案中获得的知识将为 Kerchberger博士设计和执行未来R01的建议，以使用NIH-研究ARD的功能基因组学支持的EHR生物库，例如电子病历和基因组网络以及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博士独立领导构成基础临床医生，遗传学家和数据科学家的合作团队，以进行大型基于EHR的关键研究疾病综合征将改善风险预测，使用遗传风险确定新型疾病亚型，以及最终为重症患者带来精确药物。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genome-wide association analyses of common infections in a large practice-based biobank.

DOI：
10.1186/s12864-022-08888-9
发表时间：
2022-09-27
期刊：
BMC GENOMICS
影响因子：
4.4
作者：
Jiang, Lan;Kerchberger, V. Eric;Shaffer, Christian;Dickson, Alyson L.;Ormseth, Michelle J.;Daniel, Laura L.;Leon, Barbara G. Carranza;Cox, Nancy J.;Chung, Cecilia P.;Wei, Wei-Qi;Stein, C. Michael;Feng, QiPing
通讯作者：
Feng, QiPing

Host Response to Infection: Not All Lymphopenia Is Created Equal in SARS-CoV-2.

宿主对感染的反应：SARS-CoV-2 中并非所有淋巴细胞减少症都是一样的。