心脏衰竭的肌球蛋白激活治疗

Heart failure disease, a lowered ability of the heart to move blood through the vascular system, can frequent cause of death and affect a large number of people. Cardiac myosin is the molecular motor in the heart converting chemical energy in the metabolic fuel from the food we eat into the mechanical work of pumping blood. An apparent heart failure treatment is myosin activation that relieves disease symptoms by inducing myosin to increase its power output. While myosin can move actin in vitro, its in vivo environment is crowded and constrained by the fiber lattice. The differences between the myosin machine in vivo and in vitro affects translation of its known basic characteristics to disease therapy. The marriage of in vivo and single myosin techniques to study human heart contraction in zebrafish embryo models is a multi- scaled technology developed in this proposal for basic and translational research. Our previous work has measured the single myosin leave arm orientation in live zebrafish skeletal muscle successfully, which provided a possibility to measure single myosin in beating zebrafishs’ heart. Here, we will study native myosin activation and characteristic by using the transparent zebrafish embryo model for human cardiac disease and also for drug activators to imitate. Also, a small molecular myosin binding activator, omecamtiv mecarbil (OM), which significantly increases stroke volume without increasing oxygen consumption.Results from the project study have the added bonus of providing clinically relevant insight into this therapeutic small molecule agent.

心脏衰竭通常和获得性或遗传性心肌病联系在一起，是导致心肌病病人死亡的常见原因。心脏肌球蛋白是影响心脏收缩能力的重要蛋白质之一，当前心脏衰竭的主要治疗方法是用药物激活肌球蛋白，增加其泵血的能力来缓解症状。当前对肌球蛋白的研究大多集中在体外，然而肌球蛋白的体内环境非常拥挤并且被格子状的肌纤维所束缚，限制了肌球蛋白的体外研究。基于在斑马鱼骨骼肌中成功进行的单肌球蛋白超分辨率杠杆臂定位测量技术，本研究拟通过在斑马鱼胚胎模型中的体内单分子测量技术研究心脏肌球蛋白的激活、特征以及探索药物激活剂对心脏衰竭的影响，进一步阐明能够在不增加氧气消耗的情况下，显著增加心缩排血量的小分子肌球蛋白结合激活剂Omecamtiv Mecarbil (OM) 激活肌球蛋白的机理。本课题的研究结果将对临床心力衰竭的治疗提供重要的理论依据。