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.

项目摘要 PIP2是次要的磷脂（PL），在多种细胞功能中起关键作用，但 PIP2在动脉粥样硬化和NLRP3/ IL-1炎性途径中的作用不好 特征。我先前已经表明，ABCA1充当磷脂酰肌醇4、5- 双磷酸（PIP2）氟pase，将pip2从血浆的内部传递到外部小叶 膜。 ABCA1是一种细胞胆固醇外排转运蛋白，在防止 通过排出来超过细胞的脂质/胆固醇和通过 阻止促炎途径。 ABCA1突变的人类患者患有 LDLR KO小鼠中ABCA1/G1的早产动脉粥样硬化和巨噬细胞特异性敲除 促进动脉粥样硬化和斑块炎症。促炎性NLRP3/IL-的作用 CANTOS试验强调了动脉粥样硬化中的1月注意力 遇到了主要试验终点，减少了心脏病发作，中风和 心血管死亡。最近的研究表明，Gasdermin D（GSDMD）是新的 发现的炎性体的底物与质膜上的PIP2结合 寡聚，产生用于释放成熟IL-1的孔。拟议的研究将揭示 PIP2在这些途径中的新作用，可能为热干预打开新窗口 预防心血管疾病（CVD）。该建议将进一步将PIP2建立为主要 细胞胆固醇外排的调节剂并识别PIP2 Flippase（P4型ATPases， 将PIP2从质膜的外部传递到内部传单。 胆固醇外排和炎症。该提案将确定GSDMD在 动脉粥样硬化，反向胆固醇转运（RCT），并逆转了负面影响 RCT上的炎症。该提案的三个主要目标是： 1）将PIP2建立为一个 主要的细胞胆固醇外排调节剂，2）识别和表征PIP2 Flippase和 确定P4型ATPases在胆固醇外排和注射中的作用，以及3） 确定毒气蛋白D在动脉粥样硬化和RCT中的作用。