Phosphatidylinositol Metabolism and Trafficking in Atherosclerosis and Inflammation

动脉粥样硬化和炎症中的磷脂酰肌醇代谢和运输

• 批准号: 10299698
• 负责人: Kailash Gulshan
• 金额: $ 30.78万
• 依托单位: CLEVELAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10299698
• 关键词: ATP binding cassette transporter 1; ATP phosphohydrolase; ATP8B1 gene; Antisense Oligonucleotides; Arterial Fatty Streak; Atherosclerosis; Autophagocytosis; Binding; Biological Assay; CRISPR/Cas technology; Cardiovascular Diseases; Cardiovascular system; Cell membrane; Cell physiology; Cells; Cessation of life; Cholesterol; Data; Foam Cells; Goals; Human; Hyperlipidemia; Impairment; Inflammasome; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 beta; Knock-out; Knockout Mice; Lipids; Mediating; Metabolism; Minor; Modeling; Mus; Mutation; Myocardial Infarction; Oligonucleotides; Pathway interactions; Patients; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phosphatidylserines; Phospholipids; Phosphoric Monoester Hydrolases; Plasma; Play; Regulation; Role; Small Interfering RNA; Stroke; Therapeutic Intervention; Zymosan; atheroprotective; cholesterol control; insight; knock-down; macrophage; mouse model; new therapeutic target; novel; polymicrobial sepsis; premature; premature atherosclerosis; prevent; reverse cholesterol transport; trafficking

PIP2 is a minor phospholipid (PL) and plays a critical role in variety of cellular functions but the role of PIP2 in atherosclerosis and Nlrp3/ IL-1β inflammasome pathway is not well characterized. I have previously shown that ABCA1 also 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-1β 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 inflammasome, binds to PIP2 on plasma membrane and oligomerize, generating pores for releasing mature IL-1β. 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 role of P4-type ATPases in cholesterol efflux and inflammation, and 3) to determine role of Gasdermin D in atherosclerosis and RCT.

PIP2是一种次要的磷脂（PL），在各种细胞功能中起着关键作用，但是PIP2在动脉粥样硬化中的作用和NLRP3/ IL-1 I是lammasome途径，我以前表明ABCA1也表现为ABCA1。 A，5-双磷酸盐（PIP2）Floppase，将PIP2从质膜的外部传递到质膜的外部小叶。 ABCA1患有早产的动脉粥样硬化和巨噬细胞特异性敲除abca1/g1在LDLR KO小鼠中会促进和斑块炎症。 ，最近的研究表明，GASDERMIN D（GSDMD）是一种新发现的炎症体的基板，与PIP2结合了PIP2，在质膜上和寡聚，为释放的成熟IL-1β产生了孔。这些途径上的角色可能为预防心血管疾病（CVD）打开新的新窗口。反过来，GSDMD在动脉粥样硬化中的胆固醇和炎症。 Flipppase并确定P4型在胆固醇外排和炎症中的作用），以确定Gasdermin Herosclosis和RCT的作用。