SIRPa对心肌肥厚的影响及其机制研究

Myocardial hypertrophy is one of the most important pathologic basis leading to heart failure，however the occurrence mechanism is still not clear, so treatment method is also very limited. Immune response participate myocardial remodeling, so can it become the new target of myocardial hypertrophic treatment? Signal regulatory protein a (SIRPa), belongs to the immunoglobulin receptor superfamily, is a kind of inhibitory receptor, which regulate a variety of immune response, but its role in the heart is not reported. We try to study its function in myocardial hypertrophy and its related mechanism with the animal models and cell cultivation combining with molecular biology technology. At the animal level, we use SIRPa knockout mice and heart specificity SIRPa transgenic mice to study the influence of SIRPa on myocardial hypertrophy and its possible molecular mechanism. At the cell level, we apply the recombinant adenovirus transfection technology to research the effect of SIRPa genes on rat myocardial cells and fibroblasts pathological process. At last, the molecular biology technology will be used to explain how the SIRPa genes play a role in myocardial cell hypertrophy, fibroblasts collagen synthesis processes. It is hope to supply a new theoretical basis for the therapy of myocardial hypertrophy and heart failure.

心肌肥厚是导致心力衰竭的重要病理基础,但其发生机制目前尚未完全阐明，因此治疗手段也非常有限。免疫反应参与心肌重构，调节天然免疫激活的强度能否成为治疗心肌肥厚的新靶点？信号调节蛋白 a（SIRPa），是一种调控多种免疫反应的抑制性受体，但其在心肌肥厚发生发展中的作用国内外尚未见报道。本项目拟从动物水平、细胞水平及分子水平阐明SIRPa在心肌肥厚中的作用及其具体机制。动物水平，应用SIRPa基因敲除及心脏特异性SIRPa转基因小鼠，研究SIRPa基因对小鼠心肌肥厚的影响。细胞水平，通过重组腺病毒转染技术研究SIRPa基因对大鼠原代心肌细胞、成纤维细胞功能的影响。最后运用分子生物学技术明确SIRPa基因调控心肌肥厚的具体机制。力图为心肌肥厚和心衰的临床治疗寻找新的靶点和理论依据。

临床研究表明心肌肥厚是慢性心力衰竭、冠心病等心血管疾病的独立危险因素，是心肌长期负荷过度引起的一种适应性病理改变，以心肌细胞体积增大和细胞外基质增多为特征。但目前其发生机制仍未完全阐明。本项目研究发现在扩张性心肌病患者心肌组织以及压力负荷诱导的小鼠肥厚性心肌组织和血管紧张素II刺激的心肌细胞肥厚模型中均发现信号调节蛋白a（SIRPa）表达量显著降低。通过SIRPa全身性基因敲除及心脏特异性SIRPa转基因小鼠，明确了SIRPa在心肌肥厚中的作用。进一步证实SIRPa通过与Toll样受体4直接结合可以抑制Toll样受体4/核转录因子κB（TLR4/NF-κB）信号通路从而抑制心肌肥厚，进而敲除TLR4基因可以逆转因SIRPa缺失引起的压力负荷诱导的心肌肥厚。本项目阐明了SIRPa在心肌肥厚的发生发展中作用机制与分子调控机制，为临床防治以及相关的新药开发提供了新的潜在靶点与理论依据。