Genetic Variation in the ANGPT-TIE Pathway and Risk for Acute Lung Injury

ANGPT-TIE 通路的遗传变异和急性肺损伤的风险

基本信息

批准号：
8053876
负责人：
Nuala Jennings Meyer
金额：
$ 13.71万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8053876
关键词：
ANGPT1 gene ANGPT2 gene Acute Lung Injury Affect Alveolar Angiopoietin-1 Angiopoietin-2 Angiopoietins Animals Automobile Driving Bioinformatics Candidate Disease Gene Clinical Investigator Cohort Studies Complex Genetic Trait Computational Technique Computer Analysis Computer Simulation Critical Illness DNA Resequencing Data Development EGF-Like Domain Floods Functional RNA Future Gene Proteins Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease Genetic Variation Genomics Genotype Goals Haplotypes Hypoxemia Immunoglobulins In Vitro Individual Intermediate Variables Introns Investigation Link Linkage Disequilibrium Lung Maps Mediating Mentors Methodology Modeling Molecular Biology Molecular Epidemiology Morbidity - disease rate Pathogenesis Pathway interactions Permeability Plasma Plasma Proteins Pneumonia Predisposition Proteins Research Research Design Research Personnel Risk Risk Factors Role Sepsis Subgroup Syndrome TEK gene TIE gene TIE-2 Receptor Testing Training Transfusion Translational Research Trauma United States VEGFA gene Variant Work cohort experience gene function gene interaction genetic analysis genetic epidemiology genetic risk factor genome wide association study high risk human data insertion/deletion mutation member mortality novel novel therapeutics patient oriented patient oriented research receptor tool

项目摘要

DESCRIPTION (provided by applicant): Acute lung injury (ALI) causes major morbidity and mortality in the United States. Recent data indicate a genetic component to ALI susceptibility. A better understanding of these genetic risk factors would offer mechanistic clues to ALI pathogenesis and potentially stimulate investigation of novel therapeutic avenues. In addition, identification of specific, individualized risk factors for ALI might allow future personalized therapy. Our preliminary data indicate that ANGPT2 (angiopoeitin-2) is a candidate gene associated with the development of ALI following severe trauma. The ALI-associated variant we identified and validated is intronic, and has no known function. However, this variant tags the same haplotype block identified by an independent group, providing a strong rationale to further investigate the locus for functional effects. The goals of this proposal are 1) to resequence the LD block of ANGPT2 in a subgroup of subjects who developed ALI and use advanced computational analysis to identify potential functional variants; 2) to genotype ANGPT2 variants in a large cohort of critically ill trauma subjects at risk for ALI, and test the associations between genotype and ALI and genotype and plasma protein (ANG-2) level; and 3) to test other angiopoietin pathway members (ANGPT1, TIE1, TIE2, and VEGFA) for association between genotype and ALI, both individually or through interactions with each other. Completion of this project will provide the candidate with advanced training and critical experience in cohort study design and conduct; tailoring genetic analysis at the gene and pathway level; applying advanced bioinformatic and computational techniques to identify functional sequences and test for gene-gene interaction; and applying causal pathway model analysis to determine the contribution of intermediate variables such as plasma protein level. The candidate has assembled a rich mentoring committee spanning expertise in patient-oriented research, molecular and genetic epidemiology, genomics, bioinformatics, and molecular biology. In addition, she is taking advantage of Penn's outstanding educational opportunities through a Master's in Translational Research. The proposal maps a clear plan to allow the candidate to become an independent clinical investigator in patient-oriented translational research. Acute lung injury causes significant morbidity and mortality in the United States. This research will provide new information about genetic risk factors for ALI, and will provide the primary investigator necessary training in cohort study design and novel methodologies to test for gene function and multigenic interaction.

描述（由申请人提供）：急性肺损伤 (ALI) 在美国造成重大发病率和死亡率。最近的数据表明 ALI 易感性有遗传因素。更好地了解这些遗传风险因素将为 ALI 发病机制提供机制线索，并可能刺激新治疗途径的研究。此外，识别 ALI 的具体、个体化危险因素可能有助于未来的个性化治疗。我们的初步数据表明 ANGPT2（血管生成素-2）是与严重创伤后发生 ALI 相关的候选基因。我们鉴定和验证的 ALI 相关变体是内含子，并且没有已知的功能。然而，该变体标记了由独立小组识别的相同单倍型块，为进一步研究功能效应基因座提供了强有力的理由。该提案的目标是 1) 在发生 ALI 的受试者亚组中对 ANGPT2 的 LD 模块进行重新测序，并使用先进的计算分析来识别潜在的功能变异； 2) 对一大群有 ALI 风险的危重创伤受试者中的 ANGPT2 变异进行基因分型，并测试基因型与 ALI 以及基因型与血浆蛋白 (ANG-2) 水平之间的关联； 3) 单独或通过彼此相互作用测试其他血管生成素通路成员（ANGPT1、TIE1、TIE2 和 VEGFA）的基因型与 ALI 之间的关联。完成该项目将为候选人提供队列研究设计和实施方面的高级培训和关键经验；在基因和途径水平上定制遗传分析；应用先进的生物信息和计算技术来识别功能序列并测试基因-基因相互作用；并应用因果路径模型分析来确定血浆蛋白水平等中间变量的贡献。该候选人组建了一个内容丰富的指导委员会，涵盖以患者为中心的研究、分子和遗传流行病学、基因组学、生物信息学和分子生物学方面的专业知识。此外，她还通过转化研究硕士学位利用宾夕法尼亚大学出色的教育机会。该提案制定了一个明确的计划，使候选人能够成为以患者为导向的转化研究中的独立临床研究者。在美国，急性肺损伤导致显着的发病率和死亡率。这项研究将提供有关 ALI 遗传风险因素的新信息，并将为主要研究者提供队列研究设计和测试基因功能和多基因相互作用的新方法方面的必要培训。