Tbx15介导IGF1-PI3K/AKT-mTOR自噬轴在压力超负荷诱导心肌肥厚心力衰竭中的调控机制

高血压及其并发症是我国沉重的医疗负担，压力超负荷诱导心肌肥厚心力衰竭的调控机制尚未明确。申请者前期成果发现心肌细胞自噬在压力超负荷诱导心肌肥厚心力衰竭的过程中发挥重要作用；如何调控心肌细胞自噬是其中一个关键环节。单细胞测序分析发现转录因子Tbx15在压力超负荷诱导心肌肥厚心力衰竭的过程中显著升高，并正向调控下游IGFBP5，其可能是IGF1-PI3K/Akt-mTOR自噬通路（IGF1自噬轴）的抑制蛋白，具有调控自噬的作用。据此假设：Tbx15通过IGFBP5调控IGF1自噬轴参与压力超负荷诱导心肌肥厚心力衰竭进程。首先，本课题从细胞模型和模式动物角度阐明Tbx15如何调控IGFBP5、是否通过IGF1自噬轴影响心肌细胞自噬、能否干预压力超负荷诱导心肌肥厚心力衰竭的进程。其次，通过临床研究验证IGF轴在高血压心力衰竭人群预后中的作用。本研究将为高血压心肌肥厚心力衰竭的防治提供新靶点和思路。

Hypertension and its complications are a heavy medical burden in China, and the underlying mechanism of pressure overload induced myocardial hypertrophy and heart failure has not yet been clarified. The applicant's previous study found that cardiomyocyte autophagy plays an important role in the process of pressure overload-induced cardiac hypertrophy and heart failure; how to regulate cardiomyocyte autophagy is one of the key points. Single-cell transcriptome sequencing analysis found that the transcription factor Tbx15 significantly increased during pressure overload-induced cardiac hypertrophy and heart failure, and positively regulated downstream IGFBP5, which may be an inhibitor of the IGF1-PI3K/Akt-mTOR autophagy pathway (IGF1 autophagy axis) and has the role of regulating autophagy. Pre-experimental results also demonstrate that down-regulating Tbx15 can inhibit autophagy and hypertrophy of cardiomyocytes induced by mechanical stretch. Based on these, we hypothesized that Tbx15 regulates the IGF1 autophagy axis through IGFBP5 and participates in the process of cardiac hypertrophy and heart failure induced by pressure overload. Firstly, from the perspective of cell models and model animals, this study will explain how Tbx15 regulates IGFBP5, whether it affects myocardial cell autophagy through the IGF1 autophagic axis and interferes with the process of pressure overload-induced cardiac hypertrophy and heart failure. Secondly, clinical study will verify the role of IGF1/IGFBP5 in the prognosis of patients with hypertensive heart failure. This study will provide a new target and idea for the prevention and treatment of hypertensive myocardial hypertrophy and heart failure.