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.

该项目的目的是在特定的抗氧化剂基因中鉴定功能性基因多态性和/或单倍型，这些基因与急性肺损伤（ALL）及其更严重的形式（急性呼吸遇险综合征（ARDS））相关，在重大伤害患者中。我们假设改变调节氧化剂产生和排毒的酶功能的遗传变异将增加患有严重创伤的重症患者的ALI/ARDS的风险。当前的提案建立在我们既定的队列研究基础设施基础上，该基础设施是由我们小组开发和完善的，作为先前NHLBI SCOR的ALI/ARDS的一部分。将根据实验数据检查两个关键的抗氧化剂基因（过氧化氢酶和GSTPI），这表明它们在肺部疾病中起着重要作用，并进行初步分析，这表明单核苷酸多态性（SNP）与ALI/ARDS风险增加的相关性。将研究1-CYS过氧蛋白（PRDX6），因为有越来越多的证据表明该酶在预防氧化损伤和该酶的中心位置在PO1提案中的中心位置。在AIM 1中，将在90名健康志愿者中确定过氧化氢酶，GSTPI和PRDX6基因的基因和单倍型结构。单倍型 生成的结构将用于测试目标2中ALI/ARDS风险的关联，并指导目标3的功能分析。在AIM 2中，在Catalase，GSTPI和PRDX6中候选SNP的关联与ALI/ARD的风险相关，将在患者中使用估计的635个受试者在我们的重大创伤研究中经历过大量创伤的患者（273）（273）。将检查单个SNP，单倍型和基因型相互作用的关联。在AIM 3中，使用细胞和基于动物的模型确定候选基因中观察到的SNP的功能意义。该建议将增加对ALI/ARDS发病机理的遗传基础的理解，并增加有关这些基因如何与其他相关临床危险因素相互作用的知识。这项研究的发现可能有可能用于提出旨在防止高危人群中ALD的遗传筛查策略。最后，这项队列研究将作为在未来的研究中测试ALI/ARDS中氧化应激的调节剂与其他病理生理途径的相互作用的宝贵资源。