Brg1调控脂肪细胞稳态及外周动脉疾病的分子机制研究

肥胖和糖尿病导致代谢紊乱显著增加了外周动脉疾病的发病率和致残率。在营养过剩的刺激下，脂肪细胞表型发生转化，这一过程是导致脂肪代谢稳态失衡及炎症反应加剧，继而导致外周动脉疾病发生发展的关键，但其中的表观遗传调控机制尚未阐明。Brg1是细胞中染色质重构复合物的核心成员，通过改变染色质结构从而在心血管疾病发病过程中发挥重要作用。我们前期预实验结果证实，脂肪细胞特异性敲除Brg1能够改善高脂饮食诱导的小鼠体内糖代谢紊乱和胰岛素敏感性，降低脂肪组织的炎症反应，并促进寒冷状态下机体产热和白色脂肪组织的棕色化功能。在此基础上，我们拟进一步从转录组/表观遗传组水平分析Brg1如何在高糖高脂作用下改变脂肪细胞的转录谱，并如何引起血管损伤导致外周动脉疾病。通过这一研究，我们希望阐明调控脂肪细胞稳态的新表观遗传学机制，从而为代谢性疾病和外周动脉疾病的防治提供新靶点。

Obesity and diabetes lead to metabolic disorders that significantly increase the morbidity and disability of peripheral artery disease (PAD). White adipose tissue (WAT) undergoes phenotypic switch in response to excessive nutrition, a process that underscores the disruption of lipid metabolic homeostasis, inflammation, and ultimately the development of PAD. The underlying epigenetic mechanism, however, remains to be elucidated. Brahma related gene 1 (Brg1) is the core component of the cellular chromatin remodeling complex. Brg1 plays a key role in regulating the pathogenesis of cardiovascular disease by altering chromatin structure. Our preliminary data demonstrate that adipocyte-specific deletion of Brg1 (AdipocKO) protects the mice from high-fat diet induced type 2 diabetes as evidenced by reduced body weight, attenuated WAT inflammation, improved glucose tolerance and insulin sensitivity. In addition, AdipocKO mice show enhanced heat generation and WAT browning when housed in a cold environment compared to wild type littermates. Based on these results, we intend to further investigate the role of Brg1 in regulating the WAT transcriptome under the high glucose and fat, and how to cause the pathogenesis of vascular injury and PAD. We hope to address the epigenetic mechanism underlying adipocyte homeostasis and provide a new target for the development of interventional strategies against metabolic disorders and PAD.