Title: Role of Endo180 Regulation in Tissue Fibrosis. Despite extensive research, the pathogenesis of tissue fibrosis is still incompletely understood. This is particularly true of the resolution of tissue fibrosis. The cellular degradation and remodeling of collagen, the main component of fibrotic tissue, has been proven important in regulating the severity of tissue fibrosis. Yet, the regulatory mechanisms that control this process remain largely unknown. Endo180 is the canonical collagen endocytic receptor. Genetic deletion of this receptor results in exaggerated fibrosis in experimental models in the lung, liver and kidney. The control of Endo180, however, is mostly unstudied. Our laboratory previously published an RNAi-based screen of Drosophila phagocytes that identified promising candidate genes that regulate collagen uptake in cells. In preliminary data, I have shown that two candidate genes from this screen, Myeloid Zinc Finger-1 (MZF1) and Cell division cycle-7 kinase (CDC7), regulate Endo180 expression. The research proposed in this grant application seeks to define the mechanistic bases of regulation of Endo180 by these two molecules, at the genetic and epigenetic levels. In addition, I propose to demonstrate the consequences of interfering with these pathways in in vivo models of fibrosis. The proposed research is significant because it is expected to advance our understanding of matrix biology and cell-matrix communication. In addition, this research will identify promising new pathways that can be targeted therapeutically to augment the resolution of fibrosis in human disease. This would represent a novel approach to treating fibrotic disease. The training objectives and related research activities of this proposal will provide new skills, manuscripts and pilot data related to fibrosis resolution and Endo180 regulation in mice and humans. This will be necessary to establish my independence in these areas and obtain R01 funding to advance this unique research program.
Idiopathic Pulmonary Fibrosis is a relatively common disorder of progressive scarring in the lungs that is almost uniformly fatal. The research described in this proposal seeks to understand how scarring may be reversed in diseases of fibrosis. The proposed research is relevant to public health because a detailed understanding of the mechanisms regulating cell-mediated collagen degradation can identify new therapeutic targets for the treatment of fibrotic disease that promote the resolution of fibrosis.