LKB1IP在病理性心肌肥厚中的作用及机制研究

病理性心肌肥厚是许多心血管疾病终末期共同的病理生理表现，其发病机制还不明确。LKB1IP作为抑癌基因LKB1的结合蛋白，其功能还研究很少。我们研究发现，过表达LKB1IP增加了异丙肾上腺素（ISO）诱导的心肌细胞肥大，小鼠中敲除LKB1IP减轻了ISO诱导的病理性心肌肥厚，LKB1IP通过结合并抑制PTEN磷酸酶活性来增加Akt的磷酸化。据此，我们提出假说：神经体液因子如ISO激活心肌细胞的PI3K-Akt信号通路，导致蛋白质合成增加和最终的心肌肥厚。同时，ISO 刺激可以使LKB1IP与PTEN蛋白结合，抑制其磷酸酶活性，导致Akt信号通路进一步激活，从而加重了病理性心肌肥厚。本课题拟运用多种实验方法，利用LKB1IP敲除小鼠，在细胞和动物水平上研究LKB1IP调节病理性心肌肥厚的作用机制。本研究的实施和完成，将为揭示病理性心肌肥厚发病机制提供新的思路，同时也为探索新型治疗方案提供依据。

Pathological cardiac hypertrophy is the common pathophysiological manifestation of many cardiovascular diseases. However, the pathogenesis of pathological cardiac hypertrophy is still unclear. LKB1IP, as a binding protein of tumor suppressor gene LKB1, has little research on its function at present. Our preliminary studies showed that overexpression of LKB1IP increased isoproterenol (ISO)-induced cardiomyocyte hypertrophy. Besides, knockout of LKB1IP in mice reduced ISO-induced pathological cardiac hypertrophy, and LKB1IP increased Akt phosphorylation by binding and inhibiting PTEN phosphatase activity. We therefore hypothesized that the neuro-humoral factors such as ISO activate PI3K-Akt signaling pathway in cardiac myocytes, resulting in increased protein synthesis and eventual pathological cardiac hypertrophy. At the same time, ISO can induce LKB1IP to bind with PTEN, which inhibits its phosphatase activity and further activates Akt signaling pathway, thus aggravating the pathological cardiac hypertrophy. To prove this hypothesis, this study will utilize LKB1IP knockout mice to explore the mechanism by which LKB1IP regulates the pathological cardiac hypertrophy in both cellular and animal levels by various experimental methods, thus to provide a new understanding the pathogenesis of pathological cardiac hypertrophy and a basis for exploring new treatment schemes.