Functional Genomics of Chemical-Induced Acute Lung Injury

化学引起的急性肺损伤的功能基因组学

基本信息

批准号：
8144632
负责人：
George Douglas Leikauf
金额：
$ 75.33万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-29 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8144632
关键词：
AKT1 gene Acrolein Acute Acute Lung Injury Address Ammonia Candidate Disease Gene Caring Cell Death Cell Survival Cells Cessation of life Chemicals Chlorine Chromosomes, Human, Pair 10 Diagnosis Epithelial Event Exposure to Funding Gene Proteins Gene Targeting Homologous Gene Hour Human In Vitro Inhalation Exposure Intramuscular Intraperitoneal Injections Lead Link Lung Malignant Neoplasms Methods Molecular Mouse Strains Mus PTEN gene Pathology Phenanthrolines Phosgene Phosphoric Monoester Hydrolases Plants Potassium Principal Investigator Proteins Pulmonary Edema Railroads Research Resistance Respiratory Failure Role Screening procedure Signal Transduction Signs and Symptoms Small Interfering RNA Structure of respiratory epithelium Sulfuric Acids Supportive care Testing Therapeutic Thymoma Time Toxic effect Viral Oncogene Work base bisperoxo(1,10-phenanthroline)oxovanadate(1-)chemical addition cytotoxicity functional genomics improved in vivo inhibitor/antagonist lung injury mortality mouse model protein protein interaction public health relevance repaired small molecule small molecule libraries

项目摘要

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.

描述（由申请人提供）：化学品引起的急性肺损伤（CIALI）可能是由许多利用恐怖袭击的化学威胁造成的。需要治疗来治疗几种化学威胁剂常见的急性效应和病理。尽管付出了巨大的努力，但关于吸入暴露与迟发性肺水肿、呼吸衰竭和最终死亡之间的病理事件仍有待了解。在过去的资助期间，我们开发并验证了 5 种常见化学物质（丙烯醛、氨、氯、光气和硫酸）导致急性肺损伤的小鼠模型。使用功能基因组学方法，使用 40 种小鼠品系来鉴定与暴露后生存时间相关的候选基因。我们结合这些结果构建了蛋白质相互作用网络（interactome）。在该网络中，发现了一个与 v-AKT1 胸腺瘤病毒癌基因同源物 1 (AKT1) 相关的细胞信号传导中枢（即具有多种蛋白质-蛋白质相互作用的蛋白质）。当磷酸化时，AKT1 通过灭活细胞死亡机制的成分来增强存活率。尽管在癌症中不受欢迎，但我们推断细胞存活 AKT1 活性的短期、可逆增强可能对 CIALI 治疗有益。我们随后发现，对 10 号染色体上缺失的磷酸酶和张力蛋白同源物 (PTEN) 的抑制是一种限制 AKT1 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事件来赋予对 CIALI 的抵抗力。方法：使用高内涵筛选方法，在体外施用先导化合物（包括 PTEN 抑制剂）以测试靶细胞致死性的逆转。将在 CIALI 的小鼠模型中使用 5 种化学物质测试先导化合物的致死率。总体目标：开发一种可提高多种化学物质引起的肺损伤期间生存率的疗法。公共卫生相关性：急性肺损伤可能是由许多利用恐怖袭击的化学威胁造成的。目前的治疗仍然仅限于支持性护理，没有批准用于损伤后治疗的治疗方法。总体目标是开发一种疗法，可提高由一种以上化学物质引起的急性肺损伤期间的生存率。