Functional Genomics of Chemical-Induced Acute Lung Injury

描述(由申请人提供)：化学诱导的急性肺损伤(CIALI)可由许多有助于恐怖袭击的化学威胁引起。需要治疗方法来治疗几种化学威胁剂常见的急性影响和病理。尽管进行了大量的努力，但关于吸入暴露与延迟性肺水肿、呼吸衰竭和最终死亡之间的病理事件仍有许多需要了解的地方。在过去的资助期间，我们建立并验证了5种常见化学物质(丙烯醛、氨、氯、光气和硫酸)造成的急性肺损伤小鼠模型。使用功能基因组学方法，40个小鼠品系被用来识别与暴露后存活时间相关的候选基因。我们将这些结果结合起来，构建了一个蛋白质相互作用网络(Interactome)。在这个网络中，发现了一个与v-AKT1胸腺瘤病毒癌基因同源1(AKT1)有关的细胞信号中枢(即具有几个蛋白质相互作用的蛋白质)。当AKT1被磷酸化时，AKT1通过灭活细胞死亡机制的组件来提高存活率。虽然在癌症中不受欢迎，但我们认为，短期、可逆地增强细胞存活AKT1活性在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AKT1活性的磷酸酶，在体外可以促进上皮修复，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事件而对CIALI产生抵抗。方法：采用高含量筛选方法，在体外给予先导化合物[包括PTEN抑制剂]，以测试靶细胞的致死性逆转。先导化合物将在CIALI致死小鼠模型上用5种化学物质进行测试。总体目标：开发一种在多种化学物质引起的肺损伤期间提高存活率的治疗方法。 与公共卫生相关：急性肺损伤可由许多化学威胁造成，这些威胁本身就是恐怖袭击的工具。目前的治疗方法仍然局限于支持性护理，没有批准用于侮辱后治疗的治疗方法。总体目标是开发一种治疗方法，在由多种化学物质引起的急性肺损伤期间提高存活率。

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.