过氧化物酶增殖激活受体δ（PPARδ）是核受体超家族中PPAR亚型之一，其功能尚未阐明。课题组新近发现：替米沙坦上调骨骼肌PPARδ表达，并与其减少高血压患者中糖尿病发病率、促进骨骼肌葡萄糖摄取、增加腓肠肌I型纤维含量、改善糖耐量与胰岛素敏感性相关，提示PPARδ可能在骨骼肌糖代谢中发挥重要调控作用。为阐明PPARδ作用机制，寻找可行的干预途径，本项目拟通过Cas9/SAM系统，内源性激活细胞内的PPARδ ，藉此克服基因外源导入或使用激动剂而产生的负面效应；辅以骨骼肌特异启动子mhc-2调控，将PPARδ-sgRNA靶向导入PPARδ+/+与-/-鼠骨骼肌组织内，从而明确PPARδ在骨骼肌糖代谢中的调控作用，解析其下游途径，探讨其成为恢复糖自稳态干预新靶点的可能性与可行途径。旨在阐明PPARδ与骨骼肌糖代谢关联，揭示其信号级联机制，为深入理解糖代谢紊乱发生机理，及其干预提供新的策略与依据

Peroxisome proliferator-activated receptor δ (PPARδ), member of the nuclear receptors superfamily, and its function is unclear now. In our study, we found Telmisartan up-regulating expression of PPARδ in skeletal muscle. Thus could reduce the diabetic mortality in hypertension and promote glucose uptake. We also found Telmisartan could increase content of type I fiber of gastrocnemius, improve glucose tolerance and insulin sensitivity. Our finding indicated that PPARδ may play an important role in muscle glucose metabolism. To illustrate the mechanism of PPARδ, find the possible prevention method, we will use Cas9/SAM system to activate endogenously PPARδ DNA remolding, thus to overcome the side effects of exogenous gene induction and agonist. And with the tet regulation, target import the PPARδ-sgRNA gene into the PPARδ+/+ or PPARδ-/- mice skeletal muscle, that can help us to clarify the regulating role of PPARδ in skeletal muscle glucose metabolism. This will analyze the downstream pathway; explore the possible intervention and feasible pathways of PPARδ in restoration of glucose homeostasis. And this will illustrate the connection of PPARδ and skeletal muscle, reveal the signal cascade system, and thus for deeply understanding the mechanism of abnormal glucose metabolism, providing the new principle and evidence for prevention.