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，批判性地研究将心肌细胞信号传导的这四个节点区域与心力衰竭的分子生理学联系起来的作用和机制途径。因果关系将通过结合体外和体内遗传策略来确定。这些途径与获得性心脏病和基于基因的人类扩张性心肌病的相关性将在当前SCOR项目的背景下与其他项目合作完成。最后，为了直接检验这些观察结果对人类心力衰竭形式的保真度，在这些小鼠模型系统中获得的单细胞生理观察结果的关系将与与Bill Barry合作在人类环境中获得的结果直接进行比较。总的来说，这个项目将与其他项目形成一个桥梁，这些项目将研究获得的模型系统中引起心力衰竭的信号通路的其他方面。因此，具体目的如下：在代偿性肥厚向心力衰竭转变过程中，确定应激诱导心肌细胞存活途径中关键成分的作用；2. 确定MLP[和相关的细胞骨架通路在扩张型心肌病和相关心力衰竭的遗传进展过程中的结构和功能作用；3. 探讨心衰过程中p38alpoha和p38β通路在心肌细胞肥大和凋亡中的作用；4. 阐明SR Ca2+调控通路在各种形式心脏肥厚和衰竭的功能抢救中的作用。

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.