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: 10372066
• 负责人: Kailash Gulshan
• 金额: $ 39.21万
• 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/10372066
• 关键词: ATP binding cassette transporter 1; ATP phosphohydrolase; ATP8B1 gene; Adult; American; Anabolism; Antisense Oligonucleotides; Arterial Fatty Streak; Atherosclerosis; Binding; CRISPR/Cas technology; Cardiovascular Diseases; Cardiovascular system; Cecum; Cell membrane; Cell physiology; Cell surface; Cells; Cessation of life; Cholesterol; Complement; Cost of Illness; Data; Degradation Pathway; Genetic Transcription; Goals; Health Expenditures; High Density Lipoproteins; Human; Human Cell Line; Hyperlipidemia; Impairment; Inflammasome; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 beta; Knock-out; Knockout Mice; Lipids; Mediating; Membrane; Metabolism; Minor; Modeling; Mus; Mutation; Myocardial Infarction; Pathway interactions; Patients; Phosphatidylinositol 4,5-Diphosphate; Phosphatidylinositols; Phospholipids; Plasma; Play; Productivity; Regulation; Role; Stroke; Testing; Therapeutic Intervention; Translations; Validation; cell growth regulation; chemical genetics; chronic inflammatory disease; in vivo; knock-down; lipidomics; macrophage; mouse model; new therapeutic target; novel; polymicrobial sepsis; premature atherosclerosis; prevent; reverse cholesterol transport; trafficking; transcriptome sequencing; transcriptomics; translocase

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.

项目概要 PIP2 是一种次要磷脂 (PL)，在多种细胞功能中发挥着关键作用，但 PIP2在动脉粥样硬化和Nlrp3/IL-1炎症小体通路中的作用尚不清楚 我之前已经证明 ABCA1 具有磷脂酰肌醇 4, 5- 的功能。 二磷酸 (PIP2) 软盘酶，将 PIP2 从血浆内叶转运至外叶 ABCA1 是一种细胞胆固醇流出转运蛋白，在预防中发挥着重要作用。 通过从细胞中排出多余的脂质/胆固醇来预防动脉粥样硬化和炎症 阻断促炎症途径。携带 Abca1 突变的人类患者患有此病。 Ldlr KO 小鼠过早动脉粥样硬化和巨噬细胞特异性敲除 ABCA1/G1 促进动脉粥样硬化和斑块炎症 促炎 Nlrp3/IL- 的作用。 1CANTOS 试验强调了动脉粥样硬化的途径，表明抗 IL-1β 疗法 达到了主要试验终点，即心脏病发作、中风和 最近的研究表明，Gasdermin D (GsdmD) 是一种新的药物。 发现炎症小体的底物，与质膜上的 PIP2 结合， 寡聚化，产生释放成熟 IL-1 的孔。拟议的研究将揭示这一现象。 PIP2 在这些途径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） 该提案将进一步确立 PIP2 的主要地位。 细胞胆固醇流出的调节因子，并鉴定 PIP2 翻转酶（P4 型 ATP 酶， 将 PIP2 从质膜的外层转运至内层），进而调节 该提案将确定 GsdmD 在胆固醇外流和炎症中的作用。 动脉粥样硬化、逆转胆固醇转运（RCT）以及逆转胆固醇的负面影响 该提案的三个主要目标是：1) 将 PIP2 建立为 主要细胞胆固醇流出调节剂，2) 识别和表征 PIP2 翻转酶和 确定 P4 型 ATP 酶在胆固醇流出和炎症中的作用，以及 3) 确定 Gasdermin D 在动脉粥样硬化和 RCT 中的作用。