Myocardial matrix remodeling by DDRs

描述(由申请人提供)： 这项提议将为PI提供新的培训和职业方向的重大转变，从定量生物物理学和纳米技术领域转向心血管疾病的生物医学研究。该提案将借鉴俄亥俄州哥伦布市俄亥俄州立大学戴维斯心肺研究所从事心肺研究的先驱研究员的专业知识和指导。整个实验计划旨在研究最近发现的胶原结合受体-盘状结构域受体(DDR)在心肌基质重塑中的作用。关于DDR-胶原相互作用的两个全新的事实已经从初步数据中出现：(1)DDR抑制1型胶原的纤维形成；(2)DDR识别胶原的纤维状态。这些发现促使我们通过两个特定的目的来研究DDRs在心肌基质重构中的作用： (1)仅DDR胞外区的表达如何影响胶原沉积；(2)DDRs如何调节胶原纤维状态和纤维化的发展。研究将在分子和细胞水平上进行，并对从有或没有心肌梗塞的病例中获得的人类心力衰竭组织进行研究。这些研究对于阐明DDRS重塑心肌基质的新机制具有重要意义。 这一建议将把PI的生物物理和显微专业知识与导师团队的分子和基质生物学能力结合起来，从而为生物医学研究提供两种互补的实验方法。这项应用的另一个主要目标是使PI能够获得分子和基质生物学技术方面的专业知识，以及心血管生理学方面的必要背景，以发展为生物医学的独立研究人员。

DESCRIPTION (provided by applicant): This proposal will provide new training and a significant shift in career direction for the PI from fields of quantitative biophysics and nanotechnology to biomedical research in cardiovascular diseases. The proposal will draw on the expertise and mentoring of pioneering investigators engaged in heart and lung research at the Davis Heart and Lung Research Institute at the Ohio State University in Columbus, OH. The overall experimental plan aims to investigate the role of recently discovered collagen-binding receptors, the discoidin domain receptors (DDRs) in myocardial matrix remodeling. Two fundamentally novel facts about DDR-collagen interactions have emerged from out preliminary data: (1) DDRs inhibit fibrillogenesis of collagen type 1, and (2) DDRs recognize the fibrillar state of collagen. These findings have led us to investigate the role of DDRs in myocardial matrix remodeling via two specific aims: (1) how does the expression of only the DDR extracellular domain affect collagen deposition, and (2) how do DDRs regulate the fibrillar state of collagen and development of fibrosis. Studies will be carried out at the molecular and cellular level and on human heart failure tissue obtained from cases with and without myocardial infaction. These investigations will be critical in elucidating novel mechanisms of myocardial matrix remodeling by DDRs. This proposal will combine the biophysical and microscopic expertise of the PI with the molecular and matrix biology competency of the team of mentors and thus provide two complementary experimental approaches for biomedical research. Another primary goal of this application is enable the PI to acquire expertise in the molecular and matrix biology techniques and the background necessary in cardiovascular physiology to develop as an independent researcher in biomedicine.