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

描述（由申请人提供）：急性肺损伤（ALI）在美国引起主要的发病率和死亡率。最近的数据表明，遗传因素对ALI易感性。更好地了解这些遗传危险因素将为ALI发病机制提供机制线索，并可能刺激新的治疗途径的研究。此外，识别特定的、个体化的ALI风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，ANGPT 2（血管生成素-2）是一个候选基因与严重创伤后ALI的发展。我们鉴定和验证的ALI相关变异是内含子的，并且没有已知的功能。然而，该变体标记了由独立组鉴定的相同单倍型块，为进一步研究该位点的功能效应提供了强有力的理论基础。该提案的目标是1）在发生ALI的受试者亚组中对ANGPT 2的LD阻断进行重新测序，并使用先进的计算分析来鉴定潜在的功能变体; 2）在处于ALI风险的危重创伤受试者的大队列中对ANGPT 2变体进行基因分型，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;和3）单独或通过相互作用测试其他血管生成素途径成员（ANGPT 1、TIE 1、TIE 2和VEGFA）基因型与ALI之间的关联。该项目的完成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学和计算技术来识别功能序列并测试基因-基因相互作用;并应用因果途径模型分析来确定中间变量的贡献，如血浆蛋白水平。候选人已经组建了一个丰富的指导委员会，涵盖以患者为导向的研究，分子和遗传流行病学，基因组学，生物信息学和分子生物学的专业知识。此外，她还通过翻译研究硕士学位利用宾夕法尼亚大学出色的教育机会。该提案描绘了一个明确的计划，允许候选人成为以患者为导向的转化研究的独立临床研究者。 在美国，急性肺损伤导致显著的发病率和死亡率。这项研究将提供有关ALI遗传危险因素的新信息，并将为主要研究者提供队列研究设计和新方法学方面的必要培训，以测试基因功能和多基因相互作用。

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.