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：
7293573
负责人：
George Douglas Leikauf
金额：
$ 73.86万
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/7293573
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 Condition Critical Illness Data Databases Development Diagnosis Early Diagnosis Effectiveness Elements Emergency Situation Endopeptidases 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 Genome 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 Transgenic Organisms Trauma Treatment Efficacy Triage Week Work Wound Healing base day design functional genomics functional restoration genetic linkage analysis genome wide association study 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

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.

即使没有外伤迹象，化学品暴露也会对内部目标造成严重创伤器官包括肺、心脏、胃肠道、眼睛和中枢神经系统。其中受伤时，肺损伤的程度往往对生存最为关键。化学引起的急性肺损伤 (CIALI) 可以被视为分子级联，即使在一个短暂的事件。不幸的是，CIALI 很可能是多种可能的恐怖袭击的结果包括故意爆炸化工厂、火车车厢脱轨或化学品卡车等场景劫持。高度关注的化学品包括氯、光气、硫酸、氨和丙烯醛。预测策略将需要监测形成复杂分子的多种生化指标签名。我们的目标是了解遗传、全局转录和分子事件，这些事件将提供对 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的方法。本应用的目的是确定分子 TGFα 和 FGF7 在提高这种情况下的生存率方面的机制和治疗效果。我们的中心假设是 TGFα、FGF7 和 TGFβ 信号传导之间的相互作用决定了生存并控制对 CIALI 后遗症的易感性。为了探索我们的假设，我们寻求： 1) 确定暴露于 5 种常见的控制 CIALI 的遗传决定因素和分子机制主要危险化学品：氯、光气、硫酸、氨、丙烯醛，2）评估 CIALI 期间 TGFα 和 FGF7 诱导和信号传导的治疗效果，并确定是否肺纤维化是保护的必然后遗症，并且 3) 识别分子 5种主要危险化学品在早期开发过程中各自独特的机制恰利。在该项目完成时，我们期望： 1）确定新的遗传差异，这些差异决定了对 CIALI 的敏感性，2) 识别在 CIALI 期间调制的多个代理共有的事件 3) 通过对 CIALI 产生保护作用来评估治疗的有效性，4) 确定肺部是否纤维化是 CIALI 期间激活 TGFalpha/FGF7 信号传导的不良后果，5) 开发关于 5 种主要危险化学品的选择性特征的初始化学品特定数据库。