Role of integrin alpha 8 in resolution of lung injury and repair

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 DESCRIPTION (provided by applicant): Dr. Chi Hung is trained in pulmonary and critical care medicine and has a strong clinical interest in the pathophysiology and management of pulmonary fibrosis and ARDS. His long-term goal is to become an independent physician-scientist focused on lung mesenchymal biology and their role in regulation of lung repair. To achieve this goal, he has developed a comprehensive career development program that builds on his prior training. This includes a research program focused on elucidating the roles of different lung mesenchymal cell populations in regulating lung fibrosis and repair and learning additional mouse models of lung injury. Additionally, Dr. Hung has identified a focused didactic training program, including training in the responsible conduct of biomedical research, co-mentors with complementary strengths and a long track record of collaboration, and a diverse scientific and career advisory committee. The proposed research will focus on the role integrin a8 in lung repair. Preliminary work on integrin a8 suggests it may play a dual role in lung repair: 1) contribute to fibrosis through activation of TGFß in vivo during the repair phase and 2) modulate endothelial repair. While the preliminary data support a role for integrin a8 in lung repair, it is unclear which mesenchymal population is the key effector. To address this question and to test whether different mesenchymal populations utilize integrin a8 to mediate different aspects of lung repair, Dr. Hung will evaluate lung repair through lineage-specific integrin a8 deletion in pericytes and resident fibroblasts in three proposed aims. Specific aim 1 will define the temporal and cellular distribution of integrin a8 over the course of injury. Alterations in integrin a8 expression following injury may provide important clues about its biological activity. In specific aim 2, integrin a8 deletion in the major progenitors of lung myofibroblasts pericytes and resident fibroblasts will address which population is critical for its role in fibrosis, and invitro and in vivo studies will further examine whether its function involves TGFß activation. In specifi aim 3, integrin a8 deletion in pericytes will test whether pericytes utilize integrin a8 in endotheial repair following lung injury.