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：
8650308
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 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8650308
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）在美国引起重大发病率和死亡率。最近的数据表明ALI易感性的遗传成分。对这些遗传危险因素的更好理解将为ALI发病机理提供机械线索，并可能刺激对新型治疗途径的研究。此外，确定ALI的特定，个性化的风险因素可能会允许将来的个性化治疗。我们的初步数据表明，Angpt2（Angiopoeitin-2）是与严重创伤后ALI相关的候选基因。我们确定和验证的Ali相关变体是内含的，并且没有已知的功能。但是，此变体标签与独立组确定的相同的单倍型块，提供了强大的理由，以进一步研究功能效应的基因座。该提案的目标是1）在开发ALI并使用先进的计算分析的受试者子组中重新设备ANGPT2的LD块，以识别潜在的功能变体； 2）在一大批患有ALI风险的危重创伤受试者中，基因型Angpt2变体，并测试基因型与ALI与基因型与血浆蛋白（ANG-2）水平之间的关联； 3）测试其他血管生成素途径成员（ANGPT1，TIE1，TIE2和VEGFA）之间的基因型与ALI之间的关联，无论是单独或通过相互作用。该项目的完成将为候选人提供高级培训和队列研究设计和行为的重要经验；在基因和途径水平上调整遗传分析；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（例如等离子体蛋白水平）的贡献。候选人组建了一个丰富的指导委员会，该委员会涵盖了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，她还通过翻译研究大师利用宾夕法尼亚州的杰出教育机会。该提案绘制了一个明确的计划，以使候选人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，急性肺损伤会引起明显的发病率和死亡率。这项研究将为ALI提供有关遗传危险因素的新信息，并将为研究人员提供同类研究设计的必要培训以及测试基因功能和多基因相互作用的新方法。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

von Willebrand factor and angiopoietin-2: toward an acute lung injury endothelial endophenotype?

冯维勒布兰德因子和血管生成素-2：急性肺损伤内皮内表型？

DOI：
10.1097/ccm.0b013e31824c8fad
发表时间：
2012
期刊：
Critical care medicine
影响因子：
8.8
作者：
Meyer,NualaJ;Christie,JasonD
通讯作者：
Christie,JasonD

Future clinical applications of genomics for acute respiratory distress syndrome.

DOI：
10.1016/s2213-2600(13)70134-6
发表时间：
2013-12
期刊：
The Lancet. Respiratory medicine
影响因子：
0
作者：
N. Meyer
通讯作者：
N. Meyer

The relationship between vitamin C or thiamine levels and outcomes for severe sepsis patients admitted to the ICU.

DOI：
10.1038/s41598-021-94473-1
发表时间：
2021-07-23
期刊：
Scientific reports
影响因子：
4.6
作者：
Prasad N;Grossestreuer AV;Meyer NJ;Perman SM;Mikkelsen ME;Hollander J;Gaieski DF
通讯作者：
Gaieski DF

Finding a needle in the haystack: leveraging bioinformatics to identify a functional genetic risk factor for sepsis death.

大海捞针：利用生物信息学确定脓毒症死亡的功能性遗传风险因素。