Functional Genomics of Chemical -Induced Acute Lung Injury

描述(申请人提供)：即使没有外部损伤的迹象，接触化学物质也会对内部目标器官造成严重创伤，包括肺、心脏、胃肠道、眼睛和中枢神经系统。在这些损伤中，肺损伤的程度往往是对生存最关键的。化学性急性肺损伤(CIALI)可以被看作是一种分子级联反应，即使是在短暂的事件发生后数小时和数天内也会不断增加。不幸的是，CIALI可能是多种可能情景的恐怖袭击的后果，包括故意引爆化工厂、火车车厢脱轨或劫持化学品卡车。高度关注的化学品包括氯、光气、硫酸、氨和丙烯醛。预测战略将需要监测形成复杂分子特征的多个生化指标。我们的目标是了解遗传、全球转录和分子事件，这些事件将为CIALI的机制提供见解，并可能改变或加强当前的紧急临床诊断和治疗方法。本研究的目的是探讨转化生长因子α和转化生长因子7在此条件下提高存活率的分子机制(S)和治疗效果。我们的中心假设是，TGFα、Fgf7和TGFbeta信号之间的相互作用决定了生存并控制了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，共同控制CIALI的5种主要危险化学品：氯、光气、硫酸、氨和丙烯醛；2)评估TGFpha和Fgf7在CIALI期间的诱导和信号传递的治疗效果，并确定肺纤维化是否是保护的必然后遗症；以及3)确定在CIALI的早期发展过程中，5种主要危险化学品中每一种所独有的分子机制。在这个项目完成后，我们期望：1)确定决定CIALI易感性的新的遗传差异，2)确定在CIALI期间调节的共同事件，3)通过导致CIALI保护的方法来评估治疗的有效性，4)确定肺纤维化是否是在CIALI期间激活TGFα/FGF7信号的不良后果，5)建立关于5种主要危险化学物质的选择特征的初始化学特异性数据库。

DESCRIPTION (provided by applicant): 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.