This five-year mentored research plan will provide the candidate with the opportunity to mature as a scientist and independent investigator in the Division of Cardiovascular Medicine at Stanford University. With its resources and opportunities for collaboration, the Division of Cardiovascular Medicine is an excellent environment for a young physician-scientist. The proposed project examines the role of a novel, flow-induced, endothelial-selective basic helix-loop-helix (bHLH) protein in the modulation of endothelial phenotype and is a natural extension of current studies. The alteration of endothelial phenotype by flow plays an important role in the development of vascular disease. The molecular mechanisms underlying this adaptive response remain largely undefined. We have identified a bHLH protein that may be important to this process. Dr. Thomas Quertermous, an established leader in vascular biology and a successful mentor, will serve as the program's sponsor. My advisory committee (Drs. Quertermous, James Topper, Mary Gerritsen and Philip Tsao) will provide their expertise and experience to ensure the success of this program. Distinct biomechanical forces modulate endothelial phenotype, in part, through changes in gene expression. Using transcriptional profiling, we identified the novel bHLH protein Hath6 which was significantly upregulated by laminar shear stress in cultured endothelial cells. Further work demonstrated that Hath6 expression was confined to the endothelium in vivo. With its in vitro upregulation by shear stress, its endothelial-selective expression in vivo and its classification as a bHLH transcription factor, Hath6 may regulate endothelial gene expression and thus provide an important link between flow and changes in endothelial phenotype. In this application, we propose a series of in vitro and in vivo studies to address this hypothesis. In the first specific aim, we will examine the ability of Hath6 to regulate transcription and determine its mechanism of action. In the second specific aim, we will alter Hath6 expression in vitro in order to identify genes that are regulated by Hath6. In the third specific aim, we will modulate the expression of Math6 (murine homologue of Hath6) via gene deletion strategies to assess its role in development. This body of work will illustrate how an endothelial-selective, shear-inducible transcription factor alters endothelial phenotypes/gene expression and thus may provide novel insights into the pathogenesis of vascular disease. Additionally, this project will provide the candidate with the opportunity to further his experience in molecular and vascular biology, focus on endothelial gene regulation as a research niche and build a career as an academic physician.
| Fang, Fang; Wasserman, Scott M; Torres-Vazquez, Jesus et al. (2014) The role of Hath6, a newly identified shear-stress-responsive transcription factor, in endothelial cell differentiation and function. J Cell Sci 127:1428-40 |
