The overall goal of this proposal is to understand the characteristics of Gia2-UNC5H2 interaction and define its role in events that are critical to lung development. Gia2 is expressed in the lung and is implicated in cell migration, proliferation and differentiation but also in more biologic processes such as organ development. Recently we identified an interaction between UNC5H2 and Gia2 in vitro and in vivo and showed UNC5H2 modulates Gia2 signaling. UNC5H2 is a regulator of neuronal axonal guidance molecule, which is also expressed in white blood cells and lung.
Specific Aim I : To define the critical amino acids in Gia2 that are necessary for Gia2-UNC5H2 interaction and define the critical region of TJNC5H2 for this binding.
Specific Aim II : To elucidate the site and time course of expression of UNC5H2 during growth and development of the lung in vitro and in vivo.
Specific Aim III : Define the role of Gia2-UNC5H2 in the regulation of cell migration, cell growth and branching morphogenesis in lung culture. First, a basic understanding of the regulation of Gia2-UNC5H2 pathways is likely to provide insight into lung development as well as other organs. Second, the understanding of cell migration is particularly important for immune cell migration. Excess migration of these cells induces a broad array of lung diseases including interstitial lung disease, ARDS and bronchiectasis. These diseases are responsible for a large number of deaths in the United States. Thus understanding pathways that may down regulate cell migration may have significant implications for therapeutic intervention.
