心肌细胞程序性坏死的调节通路研究

Cell death plays a vital role in multiple physiological processes. Apoptosis and necrosis are the most important forms of cell death, and programmed necrosis (necroptosis) which can be regulated, is the recently identified form of cell necrosis. Cardiomyocyte necrosis is involved in various serious cardiovascular diseases, including myocardial infarction, heart failure, arrhythmia and sudden cardiac death, and to it is of great importance to elucidate the mechanisms and protection of cardiomyocyte necrosis for the prevention and therapy of these cardiovascular diseases. Our recent findings identified that RIP3/CaMKII signaling pathway plays a central role in the regulation of cardiomyocyte necroptosis, which was published in Nat Med. Here, we hope to further investigate the network of the regulation of cardiomyocyte necroptosis, including: 1. the role of RIP1 in cardiomyocyte necroptosis, especially the function of RIP3/CaMKII signaling; 2. the mechanisms responsible for the activation of RIP3 by acute cardiac oxidative stress; 3. the role and mechanisms of MLKL in cardiomyocyte necroptosis. Based on the work of the function of RIP1, RIP3 and MLKL, we hope to set up the regulatory map of cardiomyocyte necroptosis and identify the nodal point of this process, which will provide novel target and strategy of the prevention of the necroptosis of cardiac myocytes.

细胞死亡参与多种生物学功能的调节。凋亡和坏死是最主要的两种细胞死亡方式，程序性坏死是最近发现的一种可调控的细胞坏死形式。心肌细胞坏死参与心梗、心衰、心律失常和心源性猝死等多种严重心血管疾病，研究心肌细胞坏死机制并加以保护，对这些疾病的预防治疗非常重要。申请人最近发现RIP3/CaMKII是心肌细胞程序性坏死的重要调节通路，发表于Nat Med。本研究希望以RIP3为中心，进一步完善心肌细胞程序性坏死的调节机制。内容包括：1. RIP1在心肌细胞程序性坏死中的作用及机制，尤其是RIP3/CaMKII通路的作用；2. 心脏急性氧化应激损伤活化RIP3的机制，尤其是RIP3磷酸化和细胞内转位；3. MLKL在心肌细胞程序性坏死的作用与机制。我们希望以RIP1、RIP3和MLKL作为核心，探讨各分子之间的关系，为心肌细胞程序性坏死建立完整的调节网络图，为保护心肌细胞程序性细胞坏死提供新靶点和新策略

心血管疾病是目前威胁人类健康的重要疾病，本课题针对心肌细胞程序性坏死的机制，开展了一系列研究，对心肌细胞程序性坏死及其相关细胞死亡类型的机制，及其在心血管疾病中的作用进行了研究，并且进一步的对如何保护心脏损伤进行了探索。主要研究成果包括：一方面研究了RIP3下游的CaMKII，在心肌细胞程序性坏死等死亡形式中的作用，以及如何针对此通路，保护心脏损伤性疾病；另一方面，通过进一步的探索，发现氧化应激调控心肌细胞程序性坏死和心脏损伤的机制，氧化应激损伤通过激活细胞内的PKC-delta，进而使细胞膜损伤相关分子MG53从心肌细胞分泌，进而保护心肌细胞坏死和心血管疾病。本课题不仅为心肌细胞程序性坏死的调控通路提供了更为清晰的分子机制，并且为通过调控心肌细胞程序性坏死，防治心血管疾病提供了理论基础。在本课题的资助下，我们共发表SCI论文10篇，包括Nature Cell Biology、Circulation和Circulation Research等，并且申请专利2项，培养博士后1名，研究生3名。