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)在美国导致主要的发病率和死亡率。最近的数据表明，ALI的易感性与基因有关。更好地了解这些遗传危险因素将为ALI的发病机制提供线索，并可能刺激对新的治疗途径的研究。此外，识别特定的、个体化的ALI危险因素可能使未来的个体化治疗成为可能。我们的初步数据表明，血管生成素-2(Angiopoeitin-2，ANGPT2)是与严重创伤后ALI发生相关的候选基因。我们鉴定和验证的ALI相关变体是内含子的，没有已知的功能。然而，这个变异标记了由独立小组鉴定的相同的单倍型区块，为进一步研究功能效应的基因座提供了强有力的理论基础。这项建议的目标是：1)对发生ALI的一组受试者的ANGPT2的LD区块进行重新测序，并使用先进的计算分析来确定潜在的功能变异；2)在大量有ALI风险的危重创伤受试者中对ANGPT2变异进行分型，并测试基因型和ALI与基因型和血浆蛋白(Ang-2)水平之间的关联；以及3)单独或通过相互作用来测试其他血管生成素途径成员(ANGPT1、TIE1、TIE2和VEGFA)与ALI之间的关联。该项目的完成将为候选人提供以下方面的高级培训和关键经验：队列研究设计和实施；在基因和途径水平上定制基因分析；应用先进的生物信息学和计算技术来确定功能序列和测试基因与基因的相互作用；以及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。这位候选人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方面的专业知识。此外，她正在利用宾夕法尼亚大学优秀的教育机会，通过翻译研究硕士学位。该提案制定了一个明确的计划，允许候选人在面向患者的转化研究中成为独立的临床研究员。 在美国，急性肺损伤会导致严重的发病率和死亡率。这项研究将为ALI的遗传危险因素提供新的信息，并将在队列研究设计和测试基因功能和多基因交互作用的新方法方面为主要研究人员提供必要的培训。

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.