心肌细胞源性BDNF对正常与缺血心肌作用机制及衰老对其影响的研究

Understanding functional role and mechanism of protective and survival factors which are derived from cardiac myocytes is one of key issues for regeneration of infarcted myocardium. In our prior report, we demonstrated that cardiac microvascular endothelial cells-derived BDNF（Brain derived neurotrophic factor） is able to promote angiogenesis of myocardium and plays benefit effectors in the regeneration of myocardial infarction (MI). Recently we further develop a line of cardiac myocyte conditional knockout BDNF mice. It provides us further prosibility to document functional roles of cardiac myocytes derived BDNF in cardiac physiology and phathology of ischemic myocytes. The present study is therefore designed to study: 1) the roles of cardiac myocyte conditional knockout BDNF in integrity of structure and function of heart, survival rate and the the effects of aging included in this precess in order to reveal the related mechanisms which are involved; 2) MI in young and old cardiac myocyte conditional knockout BDNF mice in order to document the role and the mechanism of cardiac myocytes derived BDNF in MI, and aging effects included in this process; 3) the targets which are identified in item-1 and -2, and the suitable window and dosage of BDNF therapy for MI and the related mechanism. The results of this study will provide novel mechanism, therapeutic targets and therapy for: ①maintaining the physiological function of heart; ②regeneration of MI; ③delay heart aging.

阐明能促进心肌细胞存活与再生的心脏内源性因子的作用机理，是再生梗死心肌的关键。在揭示：心脏微血管内皮细胞源性BDNF(脑源性神经营养因子)能促进心肌血管新生而有利于梗死心肌再生的基础上，我们又构建了心肌细胞条件敲除BDNF小鼠，使阐明心肌细胞源性BDNF对心脏生理及缺血性心肌病理的调控机理成为可能。本项目将：1）对心肌条件性敲除BDNF对心脏形态和功能，存活率与野生型的异同进行研究，以揭示心肌细胞源性BDNF在心脏结构与功能、个体存活的调控角色，及衰老对其的影响；2）对年青和年老心肌条件性敲除BDNF小鼠的心肌缺血梗死进行研究，以揭示心肌细胞源性BDNF对其的调控功能及机理，及衰老对相应功能的影响；3）依据研究内容1和2甄别的靶点，对BDNF能有效再生梗死心肌的最佳时间窗与用量，及实现疗效的机理进行研究。为：①维持心脏正常功能；②再生缺血梗死心肌；③延缓心脏衰老带来新的机理、靶点和疗法。