Rheb1-mTORC1信号通路在扩张型心肌病发病中的机制研究

扩张型心肌病（DCM）是引起心力衰竭和心律失常的原因之一，其机制并不完全清楚。我们以往的研究证实PDK1/Akt在DCM发生中起着重要作用。近期，我们进一步敲除了PDK1/Akt下游重要分子Rheb1，发现Rheb1心肌特异性敲除后的小鼠出现类似DCM患者的表型（心脏扩大、心力衰竭和心律失常）。基于以上研究结果，在本项目中我们拟开展以下方面的研究：①通过敲除和过表达Rheb1明确Rheb1与DCM的关系；②寻找Rheb1敲除导致DCM的关键分子靶点并进行挽救实验；③在人DCM心脏标本中检测Rheb1信号通路的改变。通过本项目，我们将明确Rheb1与DCM的关系，为寻找新的DCM治疗靶点提供理论依据和实验证据。

Dilated cardiomyopathy (DCM) is a common cause that leads to heart failure and arrythmia in the clinic. However,the underlying mechanism of DCM is still elusive. Our previous studies have demonstrated that PDK1/Akt play important roles in DCM. Recently, Rheb1，a downstream target of PDK1/Akt, was conditionally knockouted in adult mouse and sereval DCM phenotypes including heart dilatation, heart dysfunction and arrhythmia were observed.Based on these results,we will explore the precise molecular mechanism of how Rheb1 knockout contributes to DCM. We are planning to do the studies as follows: ①To clarify the role of Rheb1 in DCM through both loss-of-function (Rheb1 knockout) and gain-of-function (Adeno-associated virus serotype-9) experiments in vivo. ②To dissect the molecular mechanism of Rheb1 knockout leading to DCM.③To identify the changes of Rheb1 signaling pathway in human samples with DCM. Accordingly, we will identify a critical gene (Rheb1) responsible for DCM and also provide a novel theraputic approach for DCM.