Functional Genomics of Chemical -Induced Acute Lung Injury

描述（由申请人提供）：即使没有外部损伤的迹象，化学物质暴露也会对内部目标器官产生严重的创伤，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。化学诱导的急性肺损伤（CIALI）可以看作是在短暂事件发生后数小时或数天内发生的分子级联反应。不幸的是，CIALI很可能是多种恐怖袭击的结果，包括故意引爆化工厂、火车脱轨或化学卡车劫持。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特征的多种生化指标。我们的目标是了解基因、全局转录组和分子事件，这些事件将为CIALI的机制提供见解，并可以重新定向或加强当前的紧急临床诊断和治疗方法。本应用的目的是确定TGFalpha和FGF7在提高这种情况下生存的分子机制和治疗效果。我们的中心假设是TGFalpha， FGF7和TGFbeta信号传导之间的相互作用决定了生存并控制了CIALI对后遗症的易感性。为了探索我们的假设，我们寻求：1)确定暴露于5种主要危险化学品共同控制CIALI的遗传决定因素和分子机制；氯、光气、硫酸、氨和丙烯醛，2)评估TGFalpha和FGF7诱导和信号转导在CIALI期间的治疗效果，并确定肺纤维化是否是作为保护的必要后遗症，3)确定5种主要危险化学品在CIALI早期发展过程中各自独特的分子机制。本项目完成后，我们期望：1)确定确定CIALI易感性的新遗传差异，2)确定CIALI期间多种药物共同调节的事件，3)评估导致CIALI保护的治疗效果，4)确定肺纤维化是否是在CIALI期间激活TGFalpha/ fgf7信号的不良后果，5)建立5种主要危险化学品选择性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.