The long term objective of this proposal is to elucidate the mechanisms for alveolar epithelial adaptation to lung injury by focusing on the characterization of two novel alveolar type II cell (ATII) specific proteins with postulated important functions. The ATII cell manifests and regulates many specialized functions that allow resistance during and recovery from lung injury, such as the surfactant system, anti-oxidant scavenging, electrolyte and water balance, an cellular proliferation. These functions help prevent the development of alveolar collapse, oxidant mediated cellular necrosis, pulmonary edema, and epithelial repopulation respectively. Yet, many questions remain unanswered. What are the exact mechanisms regulating these known adaptive processes? Does the ATII cell display other important adaptive functions not yet identified? Preliminary data from the study of two novel ATH cell proteins, 2A3 and 3F9, demonstrates their significant upregulation by lung injury. This proposal's hypothesis is that 2A3 and 3F9 serve critical specialized functions specific for the ATH cell during lung injury.. Further characterization and functional determination of these proteins, may elucidate the mechanisms of ATH cell adaptive responses to injury. We propose to determine the kinetics of expression for both antigens during hyperoxia (Specific Aim 1), define whether exogenous tolerance-inducing agents upregulate their expression (Specific Aim 2), determine protein structure by molecular cloning (Specific Aim 3), and determine their function (Specific Aim 2), determine protein structure by molecular cloning (Specific Aim 3), and determine their function (Specific Aim 4). These studies may be of therapeutic importance by suggesting new modalities for either enhancing known alveolar specific adaptive processes to injury and development; or hopefully identifying two new ATII cell functions, amenable to modulation.
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