Phosphatidylinositol Metabolism and Trafficking in Atherosclerosis and Inflammation

项目摘要 PIP2是一种次要的磷脂(PL)，在多种细胞功能中发挥关键作用，但 PIP2在动脉粥样硬化中的作用及Nlrp3/IL-1炎症体途径的研究进展 特色化的。我以前已经证明ABCA1的功能是磷脂酰肌醇4，5- 二磷酸(PIP2)Floppase，将PIP2从血浆内叶运输到外叶 薄膜。ABCA1是一种细胞胆固醇外流转运体，在预防 动脉粥样硬化和炎症通过从细胞中排出过量的脂/胆固醇和通过 阻断促炎途径。ABCA1基因突变的人类患者患有 Ldlr KO小鼠早期动脉粥样硬化与巨噬细胞特异性ABCA1/G1基因敲除 促进动脉粥样硬化和斑块炎症。促炎因子Nlrp3/IL-3的作用 1 CANTOS试验强调动脉粥样硬化中的通路，表明抗IL-1β治疗 达到了主要试验终点，减少了心脏病发作、中风和 心血管疾病死亡。最近的研究表明，Gasdermin D(GsdmD)，一种新的 发现了炎症体的底物，与质膜上的PIP2结合，并 寡聚，产生释放成熟的IL-1的毛孔。拟议的研究将揭开 PIP2在这些通路中的新作用，可能为治疗干预打开新的窗口 预防心血管疾病(CVD)。这项提议将进一步确立PIP2作为主要 细胞胆固醇外流的调节并鉴定PIP2翻转酶(P4型ATPase 将PIP2从质膜的外叶运输到内叶)，进而调节 胆固醇外流和炎症。该提案将确定Gsdmd在 动脉粥样硬化，反向胆固醇转运(RCT)，以及在逆转 RCT上的炎症反应。这项提议的三个主要目标是：1)将PIP2建立为 主要的细胞胆固醇外流调节因子，2)鉴定和鉴定PIP2翻转酶和 确定P4型ATPase在胆固醇外流和炎症中的作用，以及3) 确定Gasdermin D在动脉粥样硬化和RCT中的作用。

Project Summary PIP2 is a minor phospholipid (PL) and plays a critical role in a variety of cellular functions but the role of PIP2 in atherosclerosis and Nlrp3/ IL-1 inflammasome pathway is not well characterized. I have previously shown that ABCA1 functions as a phosphatidylinositol 4, 5- bisphosphate (PIP2) floppase, transporting PIP2 from the inner to the outer leaflet of the plasma membrane. ABCA1, a cellular cholesterol efflux transporter, plays a major role in preventing atherosclerosis and inflammation by effluxing excess lipids/cholesterol from cells and by blocking pro-inflammatory pathways. Human patients with mutations in Abca1 suffer from premature atherosclerosis and macrophage-specific knockout of ABCA1/G1 in Ldlr KO mice promotes atherosclerosis and plaque inflammation. The role of pro-inflammatory Nlrp3/IL- 1pathway in atherosclerosis was highlighted by CANTOS trial showing that anti-IL-1β therapy met the primary trial endpoint, a reduction in a composite of heart attack, stroke and cardiovascular death. Recent studies have shown that Gasdermin D (GsdmD), a newly discovered substrate of the inflammasome, binds to PIP2 on the plasma membrane and oligomerize, generating pores for releasing mature IL-1. The proposed studies will unravel the novel roles of PIP2 in these pathways and may open new windows for therapeutic intervention to prevent cardiovascular disease (CVD). This proposal will further establish PIP2 as a major regulator of cellular cholesterol efflux and identify the PIP2 flippases (P4-type ATPases that transport PIP2 from the outer to the inner leaflet of the plasma membrane) that in turn regulate cholesterol efflux and inflammation. The proposal will identify the role of GsdmD in atherosclerosis, reverse cholesterol transport (RCT), and in reversing the negative effects of inflammation on RCT. The three main goals of this proposal are; 1) to establish PIP2 as a major cellular cholesterol efflux regulator, 2) to identify and characterize the PIP2 flippase and determine the role of P4-type ATPases in cholesterol efflux and inflammation, and 3) to determine the role of Gasdermin D in atherosclerosis and RCT.