Functional Genomics of Chemical -Induced Acute Lung Injury

即使没有外部损伤的迹象，接触化学物质也会对内部靶点造成严重创伤 器官包括肺、心脏、胃肠道、眼睛和中枢神经系统。其中 损伤后，肺损伤的程度往往是生存最关键的。化学性急性肺损伤 (CIALI)可以被视为一个分子级联，在几个小时和几天之后，甚至一个 瞬变事件。不幸的是，CIALI可能是多起恐怖袭击的后果 包括故意引爆化工厂、火车车厢脱轨或化学卡车的情景 劫机。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的多个生化指示剂 签名。我们的目标是了解基因、全球转录和分子事件 提供对CIALI机制的见解，并可能重新引导或加强当前的紧急临床 诊断和治疗的方法。这项应用的目的是确定分子 TGFα、FGF7提高该病生存率的作用机制(S)及治疗效果我们的 中心假说是TGFAlpha、Fgf7和TGFbeta信号之间的相互作用决定了 存活并控制对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、氨和丙烯醛，2)评估 CIALI期间TGFα和Fgf7的诱导及信号转导的疗效 肺纤维化作为保护的结果是必要的后遗症，以及3)确定分子 在早期开发过程中，5种主要危险化学品各自独有的机制 夏利。在这个项目完成后，我们希望：1)识别决定基因差异的新的遗传差异 对CIALI的敏感性，2)确定在CIALI期间调节的事件，这些事件对多个代理来说是共同的3) 通过CIALI中导致保护的治疗来评估治疗的有效性，4)确定是否有肺 纤维化是在CIALI期间激活TGFα/FGF7信号的不良后果，5)发展为 关于5种主要危险化学品的选择性特征的初始特定化学品数据库。

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.