Nodal pathways for cardiac failure in genetically engineered mice

这些研究将在基因工程动物模型系统的背景下，关键地检查将心肌细胞信号的这四个结节区域与心力衰竭的分子生理学联系起来的作用和机制。因果关系将使用体外和体内基于遗传的策略相结合的方法进行研究。这些途径与获得性心脏病和基于基因的人类扩张型心肌病的相关性将在当前SCOR计划的背景下与其他项目合作完成。最后，为了直接检查这些观察结果与人类心力衰竭形式的保真度，将在这些小鼠模型系统中获得的单细胞生理观察结果与与Bill Barry合作在人类环境中获得的单细胞生理观察结果进行直接比较。总而言之，这个项目将与其他项目形成桥梁，这些项目将检查获得性模型系统中导致心力衰竭的信号通路的其他方面。因此，本研究的具体目标如下：1.确定应激诱导的心肌细胞从代偿性肥大向心力衰竭转变过程中的关键成分的作用；2.确定MLP[和相关的细胞骨架通路]在遗传性扩张型心肌病及其相关心力衰竭进展过程中的结构和功能作用；3.确定p38alpoHA和p38β通路在心力衰竭过程中心肌细胞肥大和细胞凋亡中的作用；4.阐明肌浆网钙调节通路在不同形式的心肌肥厚和心力衰竭过程中的功能挽救作用。

These studies will critically examine the roles and mechanistic pathways which link these four nodal areas of cardiomyocyte signaling with the molecular physiology of heart failure in the context of genetically engineered animal model systems. Cause/effect relationships will be exacted using a combination of in vitro and in vivo genetic based strategies. The relevance of these pathways to acquired forms of heart disease and to genetically based forms of human dilated cardiomyopathy will be done collaboratively with other projects in the context of current SCOR Program. Finally, in order to directly examine the fidelity of these observations to human forms of heart failure, the relationship of single cell physiological observations obtained in these mouse model systems will be directly compared with those obtained in the human setting in collaboration with Bill Barry. Taken together, this project will form a bridge with the other projects that will examine other aspects of signaling pathways in acquired model systems which give rise to heart failure. Accordingly, the specific aims are as follows: 1. To identify the role of critical components in the stress-inducible myocyte survival pathway during the transition from compensatory hypertrophy to heart failure; 2. To determine the structural and functional role of MLP[ and related cytoskeletal pathways during the progression of genetically based forms of dilated cardiomyopathy and associated heart failure; 3. To identify the role of p38alpoha and p38beta pathways for cardiac myocyte hypertrophy and apoptosis during the course of cardiac failure; 4. To elucidate the role of SR Ca2+ regulatory pathways in functional rescue during various forms of cardiac hypertrophy and failure.