跨膜蛋白GARP在动脉粥样硬化中的作用及免疫学机制研究

GARP, a transmembrane protein, was recently identified to specifically express on the surface of activated regulatory T cells (nTregs), it promotes activation and secretion of TGF-beta by bonding with potential TGF-beta on the suface of regulatory T cells. Meanwhile, GARP interacts with transcription factor Foxp3 and produces a positive feedback loop, thereby inducing amplification of Tregs inhibition function. Our preliminary experiments indicate that the number and function of GARP+Tregs were decreased significantly in CAD patients and experimental animals, which are shown the presence of atherosclerotic lesions. We hypothesize that GARP, regarded as a target, may modulate the function of Tregs and influence the development of AS. In order to confirm the hypothesis, we intend to do: first, observe the dynamic expression of GARP on the resting or activated nTreg cells surface at different time points; second, observe the dynamic change of GARP expression in mouse AS process, and apply gene silencing and overexpression or adoptive transfer to block and strengthen GARP effect. This study will contribute to perfect the role and mechanism of GARP in the deveolpment of AS and immune inflammatory reaction, and may provide a new target for the prevention and treatment of AS.

GARP是一种最近鉴定的特异性表达于活化的调节性T细胞（Tregs）表面的跨膜蛋白，它与调节性T细胞表面潜在的TGF-β结合，促进TGF-β的活化与分泌；同时与转录因子Foxp3相互作用，形成正反馈环，放大Tregs抑制功能。我们的预实验表明，冠心病患者及AS小鼠GARP+Tregs数量及功能显著下降。我们推测，以GARP为靶点进行干预可调节Tregs功能及AS进程。为证实该假说，我们拟:1，观察静息及活化后不同时间点的Tregs表面GARP表达的动态变化；2，动态观察小鼠AS进程中nTreg细胞表面GARP表达规律，并应用基因沉默、过表达和过继转输阻断和增强GARP效应。通过本研究不仅阐明GARP在AS发生发展中的作用及免疫炎症反应机制，并可为AS防治提供前的干预靶点。

GARP 是一种最近鉴定的特异性表达于活化的调节性 T 细胞（Tregs）表面的跨膜蛋白，它与调节性 T 细胞表面潜在的 TGF-β结合，促进 TGF-β的活化与分泌；同时与转录因子 Foxp3 相互作用，形成正反馈环，放大 Tregs 抑制功能。我们的预实验表明，冠心病患者及 AS 小鼠 GARP+Tregs 数量及功能显著下降。我们推测，以 GARP 为靶点进行干预可调节 Tregs 功能及 AS 进程冠状动脉粥样硬化性心脏病患者体内CD4+CD25+GARP+ Treg细胞 表达降低，且急性冠脉综合征患者体内CD4+LAP+ Treg 细胞受损，我们还研究了血红素-1可以调节CD4+CD25+GARP+ Treg的功能，并且可能延缓冠状动脉粥样硬化的进展，在小鼠体内研究了阿托伐他汀可以通过上调GARP延缓AS的进展，以及通过鼻粘膜诱导HSP 60 蛋白通过鼻粘膜免疫小鼠，可以诱导 CD4+CD25+GARP+ 和 1 型 Treg细胞的增加，而诱导产生的 GARP+ Tregs，地高辛可以通过调节免疫功能延缓AS进展，而毛花苷C具有促AS进展的作用。。通过 本研究不仅阐明 GARP 在 AS 发生发展中的作用及免疫炎症反应机制，并可为 AS 防治提供前的干预靶点。