动脉粥样硬化斑块的局灶性分布与局部血管内皮所承载的剪应力密切相关，在斑块高发区的紊流具有低剪应力及不稳定回流等特性。我们最早报道紊流可持续激活内皮细胞脂代谢关键调节因子-SREBP；最近我们发现紊流通过SREBP上调天然免疫重要蛋白复合体-炎症小体。因此，我们推断：动脉粥样硬化斑块的发生是由于紊流活化内皮细胞SREBP-炎症小体信号通路，形成促粥样硬化微环境，招募单核细胞并使之分化成M1型巨噬细胞，最终形成泡沫细胞。为验证这一假设，本课题：1）探讨紊流诱导内皮细胞SREBP进而上调炎症小体的分子机制；2）研究内皮SREBP-炎症小体在巨噬细胞分化中的作用；3）利用内皮特异性SREBP转基因小鼠验证SREBP-炎症小体信号通路在动脉粥样硬化中的作用。本课题将为阐明动脉粥样硬化机理及其防治策略提供新的思路。

The focal nature of atherosclerosis in the arterial tree is correlated with athero-prone flow imposed on vascular endothelial cells (ECs). The flow patterns in these athero-prone regions are with low shear stress, oscillation, and reverse flow. In investigating the mechanotransduction mechanisms, we have previously reported that athero-prone flow activates sterol-regulatory element binding protein (SREBP) in ECs. Our recent data show that athero-prone flow induces inflammasome via SREBP. The induced inflammasome with ensuing pro-inflammatory responses can be mimicked by SREBP overexpression in ECs. With these pilot studies, the guiding hypothesis is that the prevalent distribution of atherosclerotic lesions is due, in part, to the flow-induced inflammasome via SREBP in ECs, resulting in an atherogenic milieu in the sub-endothelial space. Consequently, monocytes are recruited to the vessel wall and differentiated into M1 macrophage, leading to foam cell formation. To test our hypothesis, three Specific Aims are proposed: Aim 1 will study the molecular mechanism by which athero-prone flow induces SREBP, which in turn up-regulates inflammasome in ECs. Aim 2 will use an EC/monocyte co-culture system to examine the involvement of endothelial SREBP-inflammasome in the M1 transition of the macrophages. Aim 3 will use EC-specific SREBP transgenic mice to validate the role of SREBP-inflammasome in atherogenesis in vivo. Aiming at studying vascular impairment caused by the athero-prone flow, this project will establish a framework to further understand the mechano and molecular basis of vascular biology in health and disease regulated by flow.