The application proposes a career development plan for Dr David Morrow who is currently a molecular biology trained post-doctoral fellow in the Department of Surgery, University of Rochester. The immediate goal is to develop the necessary technical and academic expertise to transition to an independent investigator with a central focus on the hemodynamic forces associated with blood flow and their regulation of signaling pathways that mediate changes in cell and tissue fate. Vascular smooth muscle cell fate decisions (i.e., whether a cell differentiates, proliferates, undergoes apoptosis or migrates) play an important role in the pathogenesis of vascular disease including atherosclerosis, intimal hyperplasia and the arterial response to injury. The Hedgehog (Hh) signaling pathway, Notch receptor-ligand interactions and Vascular endothelial growth factor (VEGF) have all been implicated in vascular morphogenesis and modeling of the embryonic vasculature. Hh signaling occurs through the interaction of the Hh protein with its receptor, patched-1 (ptd) leading to activation of a transcription factor, Gli, which induces expression of downstream target genes including Ptc1 and Gli. The discovery of angiogenic activity for Hh, preferential Ptc1 expression in vascular tissue, combined with its mechanosensitivity in vascular cells and known morphogenic functions suggest that Hh might also co-ordinate vascular cell fate changes in adult tissue. Notch receptor-ligand interactions are also a highly conserved mechanism that regulates intercellular communication and directs individual vascular cell fate during embryogenesis, and more recently in adult cells following injury. The discovery that Shh acts upstream of Notch and VEGF during arterial differentiation combined with Hh regulation of Notch target genes in a variety of cell types, further support a role for Hh-Notch interactions in controlling vascular cell fate. Given these reports in the literature and our preliminary data supporting hemodynamic regulation of both Hh and Notch signaling components in SMC, our central hypothesis is that Hh mediates flow-induced changes in SMC growth (proliferation and apoptosis) and migration via regulation of VEGF/Notch signaling.
Understanding the molecular mechanisms regulating smooth muscle cell function and vascular remodeling should enable the design of novel and effective therapies for vascular disease. The proposed study fits well with the NIH mission to """"""""extend healthy life and reduce the burdens of illness and disability"""""""".
