The FastFasL system in lung injury

FastFasL 系统在肺损伤中的应用

• 批准号: 6521602
• 负责人: GUSTAVO MATUTE-BELLO
• 金额: $ 12.82万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-06 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6521602
• 关键词: CD95 molecule; adult respiratory distress syndrome; apoptosis; clinical research; cytokine; human subject; inflammation; laboratory mouse; membrane permeability; neutrophil; pathologic process; pulmonary edema; receptor binding; respiratory epithelium

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.

描述（由申请人提供）： 我的主要职业目标是成为一名独立的研究者，在急性肺损伤领域进行转化和综合研究。 急性肺损伤（acute lung injury，ALI）是以严重的嗜肺性肺泡炎和肺泡上皮广泛损伤为特征的疾病，其病因不明。 我的主要科学目标是确定Fas/FasL系统的促凋亡和促炎症功能对ALI发病机制的具体贡献。 主要假设是在ALI过程的早期，激活的肺泡巨噬细胞（AM）和支气管上皮细胞释放可溶性Fas配体（sFasL）。 sFasL与肺泡上皮细胞中的Fas（CD 95）结合导致细胞凋亡和上皮损伤。 相反，AM中Fas的激活不导致细胞凋亡，而是导致炎性细胞因子的释放。 这一假设来自我们的初步数据和文献。 目的1研究sFas在肺内的细胞来源及其释放的调控机制。 目的2探讨Fas的促凋亡功能在细菌性肺炎肺泡通透性改变中的作用。 目的3：通过构建Fas和FasL缺失的嵌合体小鼠模型，研究Fas促炎作用的特异性，并评价其对气道内FasL和雾化LPS的炎症反应。 阐明Fas/FasL系统在ALI发病机制中的作用是重要的，因为它可能导致急性呼吸窘迫综合征（ARDS）治疗策略的发展。 这些研究将在Dr.托马斯R的实验室进行。马丁在华盛顿大学（UW）。 该职业发展建议包括一个定制的培训计划，由该领域的六名专家组成的咨询委员会，包括UW的几个研究生课程的教学组成部分，以及积极参与呼吸细胞和分子生物学研究小组在UW的肺部分部。 拟议的研究将使受训者能够获得新技术，并进一步科学发展成为独立调查员。