Targeted Genomic Analysis of Coagulation Pathways in Acute Lung Injury

描述（由申请人提供）：拟议计划的长期目标是在面向患者的临床研究中发展独立的职业生涯。该计划的培训目标是培养进行转化研究所需的技能，包括临床试验和对危重疾病结果的遗传决定因素的分子流行病学调查。该奖项的科学目标是在基因组学领域开发一个应用于急性肺损伤（ALI）的研究计划。背景资料：ALI患者的不良临床结局与血浆蛋白C水平降低、血栓调节蛋白和纤溶酶原激活物抑制剂-1（派-1）水平升高相关。调节凝血和纤维蛋白溶解的基因中的几种多态性与相应蛋白质的血浆水平的变化和凝血障碍相关。新的初步数据表明，这些多态性也可能与ALI的发展和临床结局以及脓毒症患者对活化蛋白C（ARC）治疗的反应有关。我们的主要假设是蛋白C和纤溶途径基因多态性是成人和儿童ALI临床结局和严重程度的重要决定因素。在具体目标1中，我们将在最近完成的ARDS网络液体和导管治疗试验中招募的500名患者中测试这一假设。在具体目标2中，我们将前瞻性招募ALI儿童，以在危重儿童中检验这一假设。我们将在未来5年内在加州大学旧金山弗朗西斯科和奥克兰儿童医院招募315名患者。在具体目标3中，我们将确定这些多态性是否将预测正在进行的II期ARC临床试验中的ALI患者对ARC治疗的反应。实验设计：将使用高通量DNA测序技术分析DNA样本，以确定目标基因中的常见多态性。血浆样本将用于测量相关血浆蛋白浓度。将利用ARDS网络临床数据库（目标1）和前瞻性收集的数据（目标2和目标3）分析多态性和蛋白浓度与临床严重程度和结局的关系。重要性：这些研究将利用NHLBI ARDS网络临床试验的宝贵资源，对调节凝血和纤溶的基因中常见的遗传变异对临床结局的影响及其与ALI中APC治疗的相互作用进行全面分析。阳性结果将支持这些基因在成人和儿童ALI的病理生理学中的作用。公共卫生相关性：这项研究将为风险分层提供新的遗传标记。它还可能导致开发新的靶向治疗，并确定预测ALI患者对APC治疗反应的遗传标记，这是根据个体患者需求定制治疗的第一步。(End摘要）

DESCRIPTION (provided by applicant): The long-term objective of the proposed program is to develop an independent career in patient-oriented clinical research. The training goal of the program is to develop the skills required to carry out translational studies, including clinical trials, and molecular epidemiological investigations into the genetic determinants of outcomes in critical illnesses. The scientific objective of the proposed award is to develop a research program in the field of genomics as applied to acute lung injury (ALI). Background: Adverse clinical outcomes in patients with ALI are associated with decreased plasma levels of protein C, and increased plasma levels of thrombomodulin, and plasminogen activator inhibitor-1 (PAI-1). Several polymorphisms in the genes that regulate coagulation and fibrinolysis are associated with variation in the plasma levels of respective proteins and disordered coagulation. New preliminary data suggest that these polymorphisms may also be associated with the development and clinical outcomes of ALI, and the response to treatment with activated protein C (ARC) in patients with sepsis. Our primary hypothesis is that polymorphisms in genes of protein C and fibrinolysis pathways are an important determinant of clinical outcomes and severity of ALI in adults and children. In Specific Aim 1 we will test this hypothesis in 500 patients enrolled in the recently completed ARDS Network Fluid and Catheter Treatment Trial. In Specific Aim 2 we will prospectively enroll children with ALI in order to test this hypothesis in critically ill children. We will enroll 315 patients over the next 5 years at University of California San Francisco and Children's Hospital, Oakland. In Specific Aim 3 we will determine if these polymorphisms will predict the response to treatment with ARC in an ongoing phase II clinical trial of ARC in patients with ALI. Experimental Design: DNA samples will be analyzed using high throughput DNA sequencing technology to identify common polymorphisms in the genes of interest. Plasma samples will be used to measure the relevant plasma protein concentrations. Polymorphisms and protein concentrations will be analyzed for relationship to clinical severity and outcome utilizing the ARDS network clinical database (Aim 1) and the prospectively collected data (Aim 2 and Aim 3). Significance: The studies will capitalize on the valuable resources of the NHLBI ARDS network clinical trials to produce a comprehensive analysis of the effects of common genetic variations in genes regulating coagulation and fibrinolysis on clinical outcomes and their interaction with APC treatment in ALI. Positive findings would support roles for these genes in pathophysiology of ALI in adults and children. Public Health Relevance: This study will provide new genetic markers for risk stratification. It may also lead to development of novel targeted therapies and identify genetic markers that predict response to APC therapy in patients with ALI, which is an initial step towards tailoring therapy to the needs of the individual patient. (End of Abstract)