Resistin-like molecules in pulmonary fibrosis

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): Chronic progressive fibrotic lung diseases, such as idiopathic pulmonary fibrosis, remain essentially untreatable with urgent need for elucidating mechanisms to aid in discovery of novel effective therapy. These diseases involve complex and intricate interactions between both endogenous lung as well as bone marrow derived cells via a myriad of mediators, the full spectrum of which has not yet been identified. RELM¿ (resistin-like molecule ¿)/FIZZ1 (Found in Inflammatory Zone 1), a member of the resistin family of molecules is recently found to be highly induced in an animal model of lung fibrosis, and shown to activate fibroblasts with promotion of myofibroblast differentiation and enhancing their resistance to apoptotic stimuli. It is predominantly expressed by lung epithelial cells, which can be potently induced by Th2 cytokines via STAT6. Deficiency of these elements in mice diminishes lung RELM¿ expression that correlates with diminished lung fibrosis. Despite this suggestive evidence for a role in fibrosis, the precise in vivo roles of RELM¿ in fibrosis remain unclear. The central hypothesis of this project is that RELM¿ and its homologous second family member, RELM¿/FIZZ2, are induced in epithelial cells during lung injury resulting in activation of adjacent fibroblasts and promotion of myofibroblast differentiation, as well as participate in recruitment o bone marrow-derived cells. Interaction between these cellular elements initiated by these mediators leads to the promotion of fibrosis and its progression. The Aims are to, 1) analyze effects of RELM¿/¿ deficiency and overexpression on normal and injured lung, 2) evaluate the role of RELM¿/¿ in bone marrow-derived fibroblast-like progenitor cell recruitment and consequent impact on fibrosis, 3) identify their cellular receptors, primary downstream signaling pathways and regulated target genes, and 4) examine the regulation of RELM¿ gene expression in lung type II alveolar epithelial cells. The approaches will exploit a combination of biochemical and molecular tools to dissect the molecular mechanisms involved in regulating their expression, and will use the already available transgenic murine strains necessary to confirm their importance in vivo. Bone marrow chimera mice will be used to assess cell recruitment to the lung.