Functional Genomics of Chemical -Induced Acute Lung Injury

化学引起的急性肺损伤的功能基因组学

基本信息

批准号：
7662563
负责人：
George Douglas Leikauf
金额：
$ 70.5万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-29 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7662563
关键词：
Acrolein Acute Lung Injury Alveolar Alveolar Cell Ammonia Antioxidants Binding Biochemical Candidate Disease Gene Cause of Death Cell Proliferation Cell physiology Chemical Exposure Chemicals Chlorine Clinical Complex Critical Illness Data Databases Development Diagnosis Early Diagnosis Effectiveness Elements Emergency Situation Endothelial Cells Epidermal Growth Factor Receptor Epithelial Epithelial Cells Epithelium Equilibrium Event Exposure to Extracellular Matrix Eye FGFR2 gene Fibrinolysis Fibroblasts Foundations Functional disorder Gastrointestinal tract structure Gene Expression Gene Transfer Techniques Genes Genetic Genetic Determinism Goals Growth Growth Factor Hazardous Chemicals Healed Heart Homeostasis Host Defense Hour Individual Injury Ion Transport Knowledge Laboratories Lead Leukocytes Link Lung Maps Mediating Mediator of activation protein Methods Modeling Molecular Molecular Profiling Monitor Mus Natural Immunity Neuraxis Nickel Organ Outcome Ozone Pathway interactions Patients Peptide Hydrolases Phosgene Phospholipids Plants Play Population Positioning Attribute Predisposition Protein Biosynthesis Protein Tyrosine Kinase Proteins Pulmonary Edema Pulmonary Fibrosis Railroads Regulation Research Personnel Respiratory Failure Respiratory physiology Risk Role Signal Induction Signal Pathway Signal Transduction Signs and Symptoms Single Nucleotide Polymorphism Map Structural Protein Sulfuric Acids Testing Therapeutic Time Tissue-Specific Gene Expression Toxic effect Transcript Transforming Growth Factor alpha Transforming Growth Factor beta Transgenic Mice Trauma Treatment Efficacy Triage Work Wound Healing base combat design evidence base functional genomics functional restoration genetic linkage analysis genome wide association study genome-wide healing improved injury and repair innovation insight keratinocyte growth factor lung injury mortality mouse model novel novel therapeutics outcome forecast prognostic programs protein B receptor response surfactant therapeutic development

项目摘要

Even without signs of external injury, chemical exposure can produce severe trauma to internal target organs including the lungs, heart, gastrointestinal tract, eyes, and the central nervous system. Of these injuries, the extent of lung injury often is the most critical to survival. Chemical Induced Acute Lung Injury (CIALI) can be viewed as a molecular cascade mounting over hours and days subsequent to even a transient incident. Unfortunately, CIALI is a likely consequence of terrorist attacks of multiple possible scenarios including intentional detonation of chemical plants, railroad car derailment, or chemical truck hijacking. Chemicals of high concern include chlorine, phosgene, sulfuric acid, ammonia, and acrolein. Predictive strategies will require the monitoring of multiple biochemical indicators forming complex molecular signatures. Our goal is to understand the genetic, global transcriptomal, and molecular events that will provide insights into the mechanisms of CIALI and could redirect or strengthen current emergency clinical approaches to diagnosis and treatment. The objective of this application is to determine the molecular mechanism(s) and therapeutic efficacy of TGFalpha and FGF7 in enhancing survival in this condition. Our central hypothesis is that the interplay between TGFalpha, FGF7, and TGFbeta signaling determines survival and controls the susceptibility to sequelae from CIALI. To explore our hypothesis, we seek to: 1) Identify the genetic determinants and molecular mechanisms controlling CIALI common to exposure to 5 leading hazardous chemicals: chlorine, phosgene, sulfuric acid, ammonia, and acrolein, 2) Evaluate the therapeutic efficacy of TGFalpha and FGF7 induction and signaling during CIALI and determine whether pulmonary fibrosis is a necessary sequela as a consequence of protection, and 3) Identify the molecular mechanisms that are unique to each of the 5 leading hazardous chemicals during the early development of CIALI. At the completion of this project, we expect to: 1) Identify novel genetic differences that determine the susceptibility to CIALI, 2) Identify the events modulated during CIALI that are common to multiple agents 3) Evaluate the effectiveness of therapies by that lead to protection in CIALI, 4) Determine whether pulmonary fibrosis is an untoward consequence of activating TGFalpha/FGF7signaling during CIALI, 5) Develop an initial chemical specific database on the selective signatures of the 5 leading hazardous chemicals.

即使没有外部伤害迹象，化学暴露也会对内部目标产生严重的创伤器官，包括肺，心脏，胃肠道，眼睛和中枢神经系统。其中受伤，肺损伤的程度通常是生存最重要的。化学诱导的急性肺损伤（ciali）可以看作是在几个小时和几天之后的分子级联瞬态事件。不幸的是，ciali可能是恐怖袭击多重可能的结果场景包括有意爆炸化学厂，铁路脱轨或化学卡车劫持。高度关注的化学物质包括氯，磷酸，硫酸，氨和丙烯醛。预测策略将需要监测多种生化指标，形成复杂分子签名。我们的目标是了解将会了解遗传，全球转录组和分子事件提供有关ciali机制的见解，并可以重定向或加强当前的紧急临床诊断和治疗方法。该应用的目的是确定分子在这种情况下，TGFALPHA和FGF7在增强存活方面的机理和治疗功效。我们的中心假设是TGFALPHA，FGF7和TGFBETA信号之间的相互作用决定了生存并控制来自ciali后遗症的敏感性。为了探索我们的假设，我们寻求： 1）确定控制CIALI共同暴露于5的遗传决定因素和分子机制主要危险化学物质：氯，磷酸，硫酸，氨和丙烯醛，2）评估 TGFALPHA和FGF7诱导和信号传导的治疗功效，并确定是否是否肺纤维化是保护的必要后遗症，3）确定分子早期开发过程中5种主要危险化学物质中每一种都独有的机制 ciali。该项目完成时，我们期望：1）确定确定确定的新遗传差异 ciali的敏感性，2）确定在ciali期间调制的事件，这些事件是多种代理人共有的3）评估疗法的有效性，从而在CIALI中得到保护，4）确定是否肺部是否纤维化是激活ciali期间激活tgfalpha/fgf7signaling的不良后果，5）关于5种主要危险化学物质的选择性签名的初始化学特定数据库。