Targeted Genomic Analysis of Coagulation Pathways in Acute Lung Injury

急性肺损伤凝血途径的靶向基因组分析

基本信息

批准号：
7318993
负责人：
ANIL SAPRU
金额：
$ 15.12万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7318993
关键词：
Acute Lung Injury Adult Adult Respiratory Distress Syndrome Alleles Applications Grants Award Bioinformatics Biological Markers California Candidate Disease Gene Catheters Child Childhood Clinical Clinical Research Clinical Trials Clinical Trials Network Coagulation Process Coagulation Protein Disorders Critical Care Critical Illness Critically ill children DNA DNA Resequencing DNA Sequence Data Data Analyses Data Collection Databases Depth Development Enrollment Environmental Risk Factor Experimental Designs Fibrinolysis Fibrinolysis Pathway Functional disorder Gene Frequency Gene Proteins Genes Genetic Genetic Determinism Genetic Markers Genetic Polymorphism Genetic Variation Genomics Genotype Goals Incidence Individual Infection Intervention Investigation Knowledge Laboratories Lead Liquid substance Lung diseases Measurement Measures Mediator of activation protein Modeling Molecular Morbidity - disease rate Numbers Outcome Pathogenesis Pathway interactions Patients Pediatric Hospitals Pharmacogenetics Phase II Clinical Trials Phase III Clinical Trials Plasma Plasma Proteins Plasminogen Activator Inhibitor 1 Pneumonia Protein C Proteins Public Health Receptor Gene Research Research Personnel Research Subjects Resources Risk Role Sampling San Francisco Score Sepsis Sepsis Syndrome Severities Shock Stratification Techniques Technology Testing Therapeutic Intervention Thrombomodulin Training United States Universities Variant Ventilator Virulence Work abstracting activated Protein C base body system career cohort day design experience genetic association genetic epidemiology improved insight interest lung injury mortality novel patient oriented programs prospective protein structure function receptor response skills tool translational study treatment trial

项目摘要

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)

描述（由申请人提供）：拟议项目的长期目标是在以患者为导向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进行分子流行病学调查。该奖项的科学目标是开发一个应用于急性肺损伤（ALI）的基因组学领域的研究项目。背景：ALI 患者的不良临床结果与血浆蛋白 C 水平降低、血浆血栓调节蛋白和纤溶酶原激活剂抑制剂 1 (PAI-1) 水平升高有关。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变化和凝血紊乱有关。新的初步数据表明，这些多态性也可能与 ALI 的发展和临床结果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 和纤溶途径基因的多态性是成人和儿童 ALI 临床结果和严重程度的重要决定因素。在具体目标 1 中，我们将在参加最近完成的 ARDS 网络液体和导管治疗试验的 500 名患者中测试这一假设。在具体目标 2 中，我们将前瞻性地招募患有 ALI 的儿童，以便在危重儿童中检验这一假设。未来 5 年，我们将在加州大学旧金山分校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能够预测 ALI 患者正在进行的 ARC II 期临床试验中对 ARC 治疗的反应。实验设计：将使用高通量 DNA 测序技术对 DNA 样本进行分析，以识别感兴趣基因中常见的多态性。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）分析多态性和蛋白质浓度与临床严重程度和结果的关系。意义：这些研究将利用 NHLBI ARDS 网络临床试验的宝贵资源，全面分析调节凝血和纤溶的基因中常见遗传变异对临床结果的影响及其与 ALI 中 APC 治疗的相互作用。积极的发现将支持这些基因在成人和儿童 ALI 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。它还可能导致新型靶向治疗的开发，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。（摘要完）