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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：
8450810
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/8450810
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 risk variant 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）在美国是主要的发病率和死亡率。最近的数据表明，ALI易感性的遗传成分。更好地了解这些遗传风险因素将为ALI的发病机制提供线索，并有可能刺激研究新的治疗途径。此外，识别特定的、个体化的ALI风险因素可能会使未来的个性化治疗成为可能。我们的初步数据表明，ANGPT2（血管生成素-2）是与严重创伤后ALI发展相关的候选基因。我们鉴定和验证的与ai相关的变异是内含子的，没有已知的功能。然而，该变异标记了由一个独立群体发现的相同的单倍型块，为进一步研究功能效应的基因座提供了强有力的理由。本提案的目标是：1)在ALI患者亚组中对ANGPT2的LD区进行重排序，并使用先进的计算分析来识别潜在的功能变异；2)对ALI高危重症外伤患者进行ANGPT2基因分型，检测基因型与ALI、基因型与血浆蛋白（ANG-2）水平的相关性；3)检测其他血管生成素途径成员（ANGPT1、TIE1、TIE2和VEGFA）基因型与ALI之间的关联，无论是单独的还是相互作用的。该项目的完成将为候选人提供在队列研究设计和实施方面的高级培训和关键经验；在基因和通路水平裁剪遗传分析；应用先进的生物信息学和计算技术来识别功能序列和测试基因-基因相互作用；并应用因果通路模型分析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丰富的指导委员会，涵盖了面向患者的研究、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，她还利用宾大优秀的教育机会攻读转化研究硕士学位。该提案绘制了一个明确的计划，允许候选人成为一个独立的临床研究者在面向患者的转化研究。