The FastFasL system in lung injury

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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.