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：
8115795
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 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8115795
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 Development Enrollment Environmental Risk Factor Epidemiology 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 National Heart, Lung, and Blood Institute 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 Receptor Gene Research Research Personnel Research Subjects Resources Risk Role Sampling San Francisco 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 career development cohort design experience genetic association genetic epidemiology improved insight interest lung injury mortality novel patient oriented programs prospective protein structure function public health relevance receptor response response to injury 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）：拟议计划的长期目标是发展以患者为导向的临床研究的独立职业。该计划的培训目标是开发进行翻译研究所需的技能，包括临床试验，以及对重症疾病结果遗传决定因素的分子流行病学研究。拟议奖的科学目标是在基因组学领域制定研究计划，以应用于急性肺损伤（ALI）。背景：ALI患者的不良临床结局与血浆蛋白C水平降低以及血小板结合蛋白的血浆水平升高和纤溶酶原激活剂抑制剂1（PAI-1）有关（PAI-1）。调节凝血和纤维蛋白溶解的基因中的几种多态性与各个蛋白质的血浆水平和无序凝血的变化有关。新的初步数据表明，这些多态性也可能与ALI的发育和临床结果以及败血症患者的活化蛋白C（ARC）治疗的反应有关。我们的主要假设是，蛋白质C和纤维蛋白溶解途径的基因中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。在特定目标1中，我们将在500名参加最近完成的ARDS网络流体和导管治疗试验的患者中检验这一假设。在特定的目标2中，我们将前瞻性地招募ALI儿童，以检验重症儿童的这一假设。在接下来的5年中，我们将在加利福尼亚大学旧金山大学和奥克兰儿童医院招募315名患者。在特定目标3中，我们将确定这些多态性是否会预测ALI患者的II期临床试验中对ARC治疗的反应。实验设计：将使用高吞吐量DNA测序技术分析DNA样品，以鉴定感兴趣基因中的常见多态性。血浆样品将用于测量相关的血浆蛋白浓度。将分析多态性和蛋白质浓度，以利用ARDS网络临床数据库（AIM 1）和前瞻性收集的数据（AIM 2和AIM 3）分析与临床严重程度的关系和结果。意义：这些研究将利用NHLBI ARDS网络临床试验的宝贵资源，以全面分析常见遗传变异对调节凝血和纤维蛋白溶解对临床结果的基因的影响以及在ALI中与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的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。这也可能导致新的靶向疗法的发展，并确定预测ALI患者APC治疗反应的遗传标记，这是针对单个患者的需求量身定制疗法的第一步。（抽象的结尾）

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Performance of bovine pericardial valves in the pulmonary position.

牛心包瓣膜在肺位置的性能。

DOI：
10.1016/j.athoracsur.2010.06.021
发表时间：
2010
期刊：
The Annals of thoracic surgery
影响因子：
0
作者：
Shinkawa,Takeshi;Anagnostopoulos,PetrosV;Johnson,NatalieC;Watanabe,Naruhito;Sapru,Anil;Azakie,Anthony
通讯作者：
Azakie,Anthony

Early results of the "clamp and sew" Fontan procedure without the use of circulatory support.

不使用循环支持的“夹紧和缝合”Fontan 手术的早期结果。

DOI：
10.1016/j.athoracsur.2010.12.030
发表时间：
2011
期刊：
The Annals of thoracic surgery
影响因子：
0
作者：
Shinkawa,Takeshi;Anagnostopoulos,PetrosV;Johnson,NatalieC;Presnell,Laura;Watanabe,Naruhito;Sapru,Anil;Azakie,Anthony
通讯作者：
Azakie,Anthony

What's new about circulating biomarkers in pediatric acute lung disease.

小儿急性肺病循环生物标志物的最新动态。