Genetic Influence on Incidence of Acute Lung Injury

遗传对急性肺损伤发生率的影响

• 批准号: 7796690
• 负责人: Steven Mark Albelda
• 金额: $ 35.67万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7796690
• 关键词: Acute Lung Injury; Adult Respiratory Distress Syndrome; African American; Animals; Antioxidants; Archives; Area; Biological Assay; Blood specimen; Candidate Disease Gene; Cells; Clinical; Code; Cohort Studies; Critical Illness; Data; Development; Drug Metabolic Detoxication; Elements; Enrollment; Enzymes; Erythrocytes; Funding; Future; Genes; Genetic; Genetic Polymorphism; Genetic Screening; Genetic Variation; Genotype; Glutathione S-Transferase; Goals; Haplotypes; In Vitro; Incidence; Knowledge; Link; Lung diseases; Modeling; Molecular; National Heart, Lung, and Blood Institute; Oxidants; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pattern; Philadelphia; Play; Population; Populations at Risk; Positioning Attribute; Principal Investigator; Production; Promoter Regions; Protein Isoforms; Reactive Oxygen Species; Relative (related person); Research Infrastructure; Resistance; Resources; Risk; Risk Factors; Role; Sampling; Single Nucleotide Polymorphism; Source; Specific qualifier value; Structure; Subgroup; System; Testing; Trauma; Variant; base; catalase; caucasian American; cohort; experience; healthy volunteer; lung injury; metropolitan; oxidant stress; oxidative damage; peroxiredoxin; prevent; programs; promoter; prospective

The goal of this project is to identify functional gene polymorphisms and/or haplotypes in specific antioxidant genes that are associated with an increased risk of Acute Lung Injury (ALl) and its more severe form, the Acute Respiratory Distress Syndrome (ARDS), among patients with major trauma. We hypothesize that genetic variations that alter the function of enzymes that regulate oxidant production and detoxification will increase the risk of ALI/ARDS in critically ill patients who have experienced major trauma. The current proposal builds on our established cohort study infrastructure that was developed and refined by our group as part of a previous NHLBI SCOR in ALI/ARDS. Two key anti-oxidant genes (catalase and GSTpi) will be examined based on experimental data suggesting they play an important role in lung disease and preliminary analyses suggesting an association of single nucleotide polymorphisms (SNPs) with increased ALI/ARDS risk. 1-cys peroxiredoxin (PRDX6) will be studied because of the mounting evidence suggesting the importance of this enzyme in protecting against oxidative damage and the central position of this enzyme in this PO1 proposal. In Aim 1, the gene and haplotype structure of the catalase, GSTpi, and PRDX6 genes will be determined in 90 healthy volunteers. Haplotype structures generated will be used to test associations with ALI/ARDS risk in Aim 2 and guide the functional analyses of Aim 3. In Aim 2, the association of candidate SNPs in catalase, GSTpi, and PRDX6 with risk of ALI/ARDS will be determined in patients who have experienced major trauma using an estimated 635 subjects in our major trauma cohort study (273 already enrolled and 362 to be enrolled). Association of single SNP's, haplotypes and genotype interactions will be examined. In Aim 3, the functional significance of observed SNPs in the candidate genes will be determined using cell and animal-based models. This proposal will add to the understanding of the genetic basis of ALI/ARDS pathogenesis and increase knowledge about how these genes interact with other relevant clinical risk factors. The findings of this study could potentially be used to suggest genetic screening strategies aimed at preventing ALI/ARDS in at-risk populations. Finally, this cohort study will serve as a valuable resource to test the interaction of regulators of oxidant stress with other pathophysiological pathways in ALI/ARDS in future studies.

该项目的目标是鉴定与严重创伤患者中急性肺损伤（AL 1）及其更严重形式急性呼吸窘迫综合征（ARDS）的风险增加相关的特定抗氧化剂基因中的功能基因多态性和/或单倍型。我们假设，基因变异改变了调节氧化剂产生和解毒的酶的功能，这将增加经历过重大创伤的危重患者发生ALI/ARDS的风险。目前的建议建立在我们建立的队列研究基础设施上，该基础设施是由我们的小组开发和完善的，作为ALI/ARDS中先前NHLBI SCOR的一部分。两个关键的抗氧化基因（过氧化氢酶和GSTpi）将根据实验数据进行检查，这些数据表明它们在肺部疾病中起重要作用，初步分析表明单核苷酸多态性（SNP）与ALI/ARDS风险增加相关。1-半胱氨酸过氧化物酶6（PRDX 6）将被研究，因为越来越多的证据表明，这种酶在保护免受氧化损伤的重要性和这种酶在这个PO 1建议的中心位置。在目标1中，将在90名健康志愿者中确定过氧化氢酶、GSTpi和PRDX 6基因的基因和单倍型结构。单体型 所产生的结构将被用于测试与目标2中的ALI/ARDS风险的关联，并指导目标3的功能分析。在目标2中，将使用我们的重大创伤队列研究中估计的635名受试者（273名已入组，362名待入组），在经历重大创伤的患者中确定过氧化氢酶、GSTpi和PRDX 6中的候选SNP与ALI/ARDS风险的关联。将检查单个SNP、单倍型和基因型相互作用的关联。在目标3中，将使用基于细胞和动物的模型确定候选基因中观察到的SNP的功能意义。这一建议将增加对ALI/ARDS发病机制的遗传基础的理解，并增加关于这些基因如何与其他相关临床危险因素相互作用的知识。这项研究的结果可能被用来建议遗传筛查策略，旨在预防高危人群中的ALI/ARDS。最后，这项队列研究将作为一个有价值的资源，以测试在未来的研究氧化应激与其他病理生理途径的调节ALI/ARDS的相互作用。