Glycogen Synthase Kinase (GSK)-3b inhibition Mediates Lymphangiogenesis to Ameliorate Experimental Fibrosis.

Brigham And Women'S Hospital, Boston MA

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Abstract

Project Summary/Abstract The goals of this proposal are to investigate molecular mechanisms of lymphangiogenesis and, subsequently, improve our current understanding of the contribution of lymphatics to the development of idiopathic pulmonary fibrosis (IPF). IPF is a devastating chronic lung disease that leads to death in 3 to 5 years in the absence of lung transplantation. Our understanding of the pathophysiology of IPF is incomplete. Treatment options are limited to supportive care, lung transplantation, or medical therapies that do not resolve but rather slow the progression of disease. There is an urgent need to improve our understanding of cellular and molecular mechanisms contributing to IPF pathogenesis in order to develop new therapeutic options. The proposed project will improve our understanding of the mechanisms of lymphangiogenesis through the investigation of glycogen synthase kinase (GSK)3-?, a multifunction serine/threonine kinase that is a critical intermediary in gene expression as well as cell growth and proliferation. Cell based assays and in vivo experiments in an animal model of fibrosis will be used to better explain the contribution of lymphatic biogenesis to tissue remodeling similar to what is observed in patients with IPF. By determining the role lymphatics play in the development of lung fibrosis, this work will determine if lymphangiogenesis is a therapeutic target in IPF. The proposed project describes a 2-year research fellowship program that will allow the principle investigator to begin an academic career in Pulmonary Medicine. Dr. Souheil El-Chemaly, an expert in lymphatic biology and interstitial lung disease, will serve as the primary sponsor to the principle investigator during the development of his scientific career. Dr. El-Chemaly is a well-respected faculty member in the Division of Pulmonary and Critical Care Medicine at Brigham and Women's Hospital. Also serving as co-sponsor will be Dr. Ivan Rosas, an expert in the field of interstitial lung disease and pre-clinical models of lung fibrosis at Brigham and Women's Hospital. Dr. Rosas has been extremely successful in mentoring fellows into independent investigators. The principle investigator will also benefit from the expertise of other highly accomplished members of his scientific advisory committee and have access to comprehensive resources available both within the Division of Pulmonary and Critical Care Medicine as well as the broad Harvard biomedical community. This project will not only serve as a critical step in the principle investigator's career development but will also provide a basis for future work as he moves from fellowship to junior faculty and, eventually, to an independent NIH funded investigator.