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

• 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
• 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

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.

即使没有外部损伤的迹象，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。这些 肺损伤的程度往往是生存的最关键。化学性急性肺损伤 （CIALI）可以被看作是一个分子级联安装在数小时和数天后，即使是一个 短暂事件。不幸的是，CIALI可能是多种可能的恐怖袭击的后果。 包括故意引爆化工厂、火车出轨或化学品卡车等场景 劫机高度关注的化学品包括氯气、光气、硫酸、氨和丙烯醛。 预测策略将需要监测多个生化指标形成复杂的分子 签名.我们的目标是了解遗传、全球转录组和分子事件，这些事件将 提供CIALI机制的见解，并可以重新定向或加强目前的紧急临床 诊断和治疗的方法。本申请的目的是确定分子量。 TGF α和FGF 7在提高这种病症中的存活率中的机制和治疗功效。我们 中心假设是TGF α、FGF 7和TGF β信号传导之间的相互作用决定了 生存和控制CIALI后遗症的易感性。为了探索我们的假设，我们试图： 1)确定控制CIALI的遗传决定因素和分子机制， 主要危险化学品：氯气、光气、硫酸、氨和丙烯醛，2）评估 CIALI期间TGF α和FGF 7诱导和信号传导的治疗功效，并确定是否 肺纤维化是一种必要的后遗症，作为保护的结果，和3）确定分子 在早期开发过程中，5种主要危险化学品的独特机制 夏利。在这个项目完成后，我们希望：1）确定新的遗传差异，决定 对CIALI的易感性，2）识别CIALI期间调节的事件，这些事件是多种药物共同的3） 评价治疗的有效性，导致保护CIALI，4）确定是否肺 纤维化是在CIALI期间激活TGF α/FGF 7信号传导的不利后果，5）发展成一种 关于5种主要危险化学品的选定特征的初步化学品数据库。