Hypoxia-Induced Mitogenic Factor in Perinatal Lung

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DESCRIPTION (provided by applicant): The long-term interest of this research program is to understand and explore the cellular and molecular mechanisms of hypoxia-induced mitogenic factor (HIMF), a protein we found in a mouse model of hypoxia-induced pulmonary hypertension, in lung development and maturation. It was also called FIZZ1 (found in inflammatory zone) in an asthma model in the lung. HIMF belongs to a new family of cysteine rich cytokines known to be specifically expressed in hypoxic and inflammatory lung. Most importantly, HIMF is highly upregulated in the developing lung during the perinatal period. This proposal will focus on two major areas. First, it will address HIMF gene expression in the developing lung, especially during the perinatal period. Second, it will investigate the cellular and molecular mechanisms of action of HIMF gene product in lung development and maturation and its relation with bronchopulmonary dysplasia (BPD) and respiratory distress syndrome (RDS). The first aim will address the hypothesis that HIMF is expressed in the developing lung and regulates pulmonary vascular development, controls maturation of the parenchymal lung, and coordinates vascularization and alveolarization. We will investigate the temporal-spatial expression of HIMF in the developing lung and its relationship with vasculogenesis and alveolarization using histological and molecular biological techniques. The second aim will examine the hypothesis that HIMF plays an important role in the maturation of the lung; disrupting HIMF gene expression might result in delayed lung development/maturation, and bronchopulmonary dysplasia (BPD). This aim will define the roles of HIMF in vascularization and alveolarization during the perinatal period in cultured (in vitro) and transplanted (in vivo) embryonic and neonatal lungs treated with HIMF protein, HIMF neutralizing antibody, or HIMF gene knock down with RNA interference (RNAi) techniques. The third aim will address the hypothesis that HIMF gene expression in the developing lung is regulated by transcription factors, including C/EBPot and HIF-2a. It will utilize comprehensive promoter-reporter transfection studies, EMSA, footprinting, and overexpression studies to define the protein-DNA interactions critical to HIMF gene expression during the perinatal period.