This application requests five years of additional support for a Program Project that is currently in year 25. The theme for the program is cellular and molecular biology of the alveolar epithelium with emphasis on the lung surfactant system. The hypothesis is that the surfactant cell cycle is regulated through control of lipid and protein synthesis, packaging in secretory organelles, regulated and constitutive secretion, cellular reuptake, and intracellular processing of endocytosed lipid and protein components. This hypothesis will be studied through 4 continuing and 2 new projects The 1st project is a continuing project that will evaluate the interaction of SP-A with alveolar type II cells and macrophages with emphasis on receptor-mediated uptake, pathways for routing to lamellar bodies, and intracellular degradation. This project will utilize SP-A """"""""knockout"""""""" mice provided by Dr. S. Hawgood. The 2nd project will focus on molecular and function studies of ABC A3, a novel transport protein that appears to be associated with the lamellar body membrane. This new project represents continuation of work currently supported as part of Project 1. The 3rd project is a new project that will investigate the role of communication between alveolar type I and type II cells through GAP junctions on surfactant secretion. The project will utilize inhibitors and molecular manipulation of connexin expression. The 4th project has as its focus the regulation of gene expression for surfactant protein B with emphasis on the role of TGFbeta and several transcription factors. The 5th project has as its focus the conversion of the primary translation product to the mature protein. This project has identified a novel pathway to aggresome formation due to misprocessing of SP-C. The 6th project will continue study of aiPLA2, a novel lysosomal-type phospholipase that is involved in DPPC synthesis and degradation and was identified during the current project. The six projects are supported by a cell culture core that provides primary cultures of granular pneumocytes as well as cultured cell lines, an imaging and cryoultramicroscopy, a new gene expression core that will engineer adenovector constructs and provide expressed normal and mutant proteins, and an administrative core. These projects and cores form a cohesive unit with extensive interactions between investigators and projects, all focused on the common aim to understand the cellular and molecular biology of the lung surfactant system.
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