The FastFasL system in lung injury

描述(由申请人提供)： 我的主要职业目标是成为一名在急性肺损伤领域进行转化性和综合性研究的独立调查员。急性肺损伤(ALI)的特征是严重的中性粒细胞肺泡炎和广泛的肺泡上皮损伤，两者的病因都不清楚。我的主要科学目标是确定Fas/FasL系统的促凋亡和促炎功能在ALI发病机制中的具体作用。主要假说是ALI早期活化的肺泡巨噬细胞(AM)和支气管上皮细胞释放可溶性Fas配体(SFasL)。肺泡上皮细胞中sFasL与Fas(CD95)结合可导致细胞凋亡和上皮损伤。相反，AM中Fas的激活并不会导致细胞凋亡，反而会导致炎性细胞因子的释放。这一假设是从我们的初步数据和文献中得出的。目的1研究肺空气中sFass的细胞来源和控制其释放的机制。目的2探讨Fas的促凋亡作用在细菌性肺炎肺泡通透性改变中的作用。目的通过建立Fas或FasL缺失的嵌合小鼠，观察其对气管内FasL或雾化内毒素的炎症反应，探讨Fas的致炎作用。阐明Fas/FasL系统在ALI发病机制中的作用非常重要，因为它可能导致急性呼吸窘迫综合征(ARDS)的治疗策略的发展。这些研究将在华盛顿大学托马斯·R·马丁博士的实验室进行。这项职业发展建议包括一个定制的培训计划，该计划包括一个由该领域六名专家组成的咨询委员会，一个教学部分，包括在威斯康星州大学的几个研究生课程，以及积极参与该大学肺科的呼吸细胞和分子生物学研究小组。拟议的研究将使受训人员能够获得新技术，并进一步从科学上发展成为一名独立的调查员。

DESCRIPTION (provided by applicant): My main career goal is to become an independent investigator performing translational and integrative research in the field of acute lung injury. Acute lung injury (ALI) is characterized by severe neutrophilic alvelitis and extensive injury to the alveolar epithelium, both of unclear cause. My main scientific goal is to determine the specific contributions of the pro-apoptotic and pro-inflammatory functions of the Fas/FasL system to the pathogenesis of ALI. The main hypothesis is that early in the course of ALI, activated alveolar macrophages (AM) and bronchial epithelial cells release soluble Fas-ligand (sFasL). Binding of sFasL to Fas (CD95) in alveolar epithelial cells results in apoptosis and epithelial damage. In contrast, activation of Fas in AM does not result in apoptosis, but instead leads to release of inflammatory cytokines. This hypothesis is derived from our preliminary data and the literature. Aim 1 investigates the cellular sources of sFasLin the airspaces of the lung and the mechanisms that control its release. Aim 2 investigates the specific role of the proapoptotic function of Fas in the development of alveolar permeability changes during bacterial pneumonia. Aim 3 investigates the specific role of the pro-inflammatory function of Fas, by generating chimeric mice lacking either Fas or FasL in key target cells, then evaluating the inflammatory response to either intratracheal FasL or aerosolized LPS. Clarifying the role of the Fas/FasL system in the pathogenesis of ALI is important because it could lead to the development of therapeutic strategies for the Acute Respiratory Distress Syndrome (ARDS). These studies will be performed at the laboratory of Dr. Thomas R. Martin at the University of Washington (UW). This career development proposal includes a customized training program consisting of an advisory committee composed of six experts in the field, a didactic component including several graduate courses at the UW, and active participation in the Respiratory Cell and Molecular Biology Study Group at the Pulmonary Division of the UW. The proposed studies will allow for the acquisition of new techniques and further scientific development of the trainee into an independent investigator.