Functional Genomics of Chemical-Induced Acute Lung Injury

描述（由申请人提供）：化学品引起的急性肺损伤（CIALI）可能是由于许多化学品威胁，利用自己的恐怖袭击。需要治疗几种化学威胁剂常见的急性效应和病理。尽管进行了大量的努力，但仍有许多关于吸入暴露与迟发性肺水肿、呼吸衰竭和最终死亡相关的病理事件有待了解。在过去的资助期间，我们开发并验证了5种常见化学品（丙烯醛、氨、氯、光气和硫酸）的急性肺损伤小鼠模型。使用功能基因组学方法，使用40个小鼠品系来鉴定与暴露后存活时间相关的候选基因。我们结合这些结果构建了一个蛋白质相互作用网络（interactome）。在该网络中，发现了涉及v-AKT 1胸腺瘤病毒癌基因同源物1（AKT 1）的细胞信号传导中心（即具有几种蛋白质-蛋白质相互作用的蛋白质）。当磷酸化时，AKT 1通过灭活细胞死亡机制的组分来增强存活。虽然在癌症中不受欢迎，但我们推断，细胞存活AKT 1活性的短期可逆增强在CIALI治疗中可能是有益的。我们随后发现，抑制10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）（一种限制AKT 1活性的磷酸酶）可增强体外上皮修复，并在体内防止CIALI。假设：抑制PTEN活性将通过激活促进细胞存活的信号传导事件来赋予对CIALI的抗性。方法：使用高含量筛选方法，将在体外施用先导化合物[包括PTEN抑制剂]以测试靶细胞中致死性的逆转。将在CIALI致死小鼠模型中使用5种化学品检测先导化合物。总体目的：开发一种治疗方法，提高多种化学品诱导的肺损伤的生存率。 公共卫生相关性：急性肺损伤可能是由许多化学威胁造成的，这些化学威胁有助于恐怖袭击。目前的治疗仍然局限于支持性护理，没有批准的治疗方法用于损伤后治疗。总体目标是开发一种治疗方法，提高一种以上化学品引起的急性肺损伤的生存率。

DESCRIPTION (provided by applicant): Chemical-induced acute lung injury (CIALI) can result from numerous chemical threats that avail themselves to terrorist attacks. Therapies are needed to treat the acute effects and pathologies that are common to several chemical threat agents. Despite intensive effort, much remains to be understood regarding pathological events linking Inhalation exposures to delayed pulmonary edema, respiratory failure, and ultimately death. In past funding period we developed and validated mouse models of acute lung injury to 5 common chemicals (acrolein, ammonia, chlorine, phosgene, and sulfuric acid). Using a functional genomics approach, 40 mouse strains were used to identify candidate genes associated with survival time following exposure. We combined the results to build a protein interaction network (interactome). Within this network, a cell signaling hub (i.e. a protein with several protein-protein interactions) was uncovered that implicated v- AKT1 thymoma viral oncogene homolog 1 (AKT1). When phosphorylated, AKT1 enhances survival by inactivating components of the cell death machinery. Although undesirable in cancer, we reasoned that short-term, reversible enhancement of the cell survival AKT1 activity could be beneficial in CIALI treatment. We subsequently found that inhibition of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a phosphatase that limits AKT1 activity, enhances epithelial repair in vitro and protect against CIALI in vivo. Hypothesis: Inhibition of PTEN activity will impart resistance to CIALI by activating signaling events that promote cell survival. Approach: Using a high content screening method, lead compounds [including a PTEN inhibitor] will be administered in vitro to test reverse of lethality in target cells. Lead compounds will be tested in mouse models of lethality from CIALI with 5 chemicals. Overall Objective: To develop a therapy that improves survival during lung injury induced by multiple chemicals. Public Health Relevance: Acute lung injury can result from numerous chemical threats that avail themselves to terrorist attacks. Current therapy remains limited to supportive care with no approved therapeutic for post insult treatment. The overall objective is to develop a therapy that will improve survival during acute lung injury induced by more than one chemical.