Cholesterol efflux, CHIP and inflammasome activation

胆固醇外流、CHIP 和炎症小体激活

基本信息

批准号：
10735980
负责人：
ALAN richard TALL
金额：
$ 61.69万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735980
关键词：
ATP binding cassette transporter 1 Acceleration Adverse effects Anti-Inflammatory Agents Area Arterial Fatty Streak Atherosclerosis Binding Cells Cholesterol Colchicine Collaborations Collagen Complex DUSP6 protein Development Dyslipidemias Enzymes Goals Grant Hematopoiesis High Density Lipoproteins Human Inflammasome Inflammation Inflammatory Infusion procedures Knock-out Lesion Link Low-Density Lipoproteins Macrophage Maps Mediating Methylation Morbidity - disease rate Movement Mus Mutation Myeloid Cells Pathway interactions Phosphoric Monoester Hydrolases Phosphorylation Population Precision therapeutics Predisposition Process Research Residual state Risk Factors Role Signal Pathway Signal Transduction Specificity Sphingomyelinase Transplantation atherogenesis calmodulin-dependent protein kinase II cholesterol trafficking clinical application endoplasmic reticulum stress extracellular improved in vivo induced pluripotent stem cell inhibitor insight mortality neutrophil novel novel strategies promoter reconstitution success ubiquitin isopeptidase

项目摘要

Project Summary/Abstract Atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality in the US. Despite the benefits of LDL lowering therapies, there remains a large burden of residual CVD, related to persistent dyslpidemia and inflammation. Even though CANTOS and colchicine trials have established the benefit of anti-inflammatory therapies, these approaches were associated with a significant increase in infectious complications, limiting their clinical application. This suggests the need for a deeper understanding of the links between dyslipidemia and atherosclerotic inflammation, leading to more effective targeting of relevant mechanisms and susceptible populations. This grant has supported studies of the mechanisms linking defective cholesterol efflux pathways to macrophage and neutrophil inflammatory processes, including NLRP3 inflammasome activation and neutrophil extracellular trap (NET) formation. We recently discovered a new pathway linking macrophage cholesterol accumulation (mediated through defective cholesterol efflux or loading with modified LDL) to ER cholesterol accumulation and activation of a signaling pathway that leads to deubiquitylation and assembly of the NLRP3 inflammasome. Inhibition of this pathway with the deubiquitinase inhibitor holomycin led to reduced atherosclerosis and NETosis, suggesting a new approach to reducing inflammasome activation and atherosclerosis. The same pathway appears to be activated in TET2 clonal hematopoiesis. The proposed studies will further explore the role of the newly defined pathway in promoting NLRP3 inflammasome activation and atherosclerosis in hyperlipidemic mice with defective cholesterol efflux or TET2 clonal hematopoiesis and in human cells containing TET2 mutations. The ability of reconstituted HDL to promote cholesterol efflux and to reverse inflammasome activation, leading to plaque stabilization, will also be investigated. The proposal should provide new mechanistic insights into the links between macrophage cholesterol accumulation and plaque inflammation and will evaluate novel precision therapeutic approaches to atherosclerosis.

项目概要/摘要动脉粥样硬化性心血管疾病仍然是导致人们发病和死亡的主要原因美国。尽管降低 LDL 疗法有好处，但仍然存在巨大的残留负担 CVD，与持续性血脂异常和炎症有关。尽管 CANTOS 和秋水仙碱试验已经证实了抗炎疗法的益处，这些方法与感染并发症的显着增加相关，限制了其临床应用。这表明需要更深入地了解血脂异常与动脉粥样硬化炎症，导致更有效地针对相关机制和易感人群。这笔赠款支持了将缺陷联系起来的机制的研究胆固醇流出巨噬细胞和中性粒细胞炎症过程的途径，包括 NLRP3 炎性体激活和中性粒细胞胞外陷阱 (NET) 形成。我们最近发现了一条连接巨噬细胞胆固醇积累的新途径（通过有缺陷的胆固醇流出或装载修饰的低密度脂蛋白）导致内质网胆固醇积累和信号通路的激活导致 NLRP3 去泛素化和组装炎症小体。用去泛素酶抑制剂全霉素抑制该途径导致减少动脉粥样硬化和 NETosis，提出一种减少炎症小体的新方法激活和动脉粥样硬化。 TET2 克隆中似乎激活了相同的途径造血作用。拟议的研究将进一步探讨新定义的途径的作用促进高脂血症小鼠 NLRP3 炎症小体激活和动脉粥样硬化胆固醇流出或 TET2 克隆造血缺陷以及含有 TET2 的人类细胞突变。重组 HDL 促进胆固醇流出和逆转的能力还将研究导致斑块稳定的炎症小体激活。提案应该为巨噬细胞胆固醇之间的联系提供新的机制见解积聚和斑块炎症，并将评估新型精准治疗方法到动脉粥样硬化。

项目成果

期刊论文数量（26）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Cholesterol accumulation in macrophages drives NETosis in atherosclerotic plaques via IL-1β secretion.

DOI：
10.1093/cvr/cvac189
发表时间：
2023-05-02
期刊：
Cardiovascular research
影响因子：
10.8
作者：
通讯作者：

BRCC3-Mediated NLRP3 Deubiquitylation Promotes Inflammasome Activation and Atherosclerosis in Tet2 Clonal Hematopoiesis.

BRCC3 介导的 NLRP3 去泛素化促进 Tet2 克隆造血过程中炎症小体激活和动脉粥样硬化。

DOI：
10.1161/circulationaha.123.065344
发表时间：
2023
期刊：
Circulation
影响因子：
37.8
作者：
Yalcinkaya,Mustafa;Liu,Wenli;Thomas,Leigh-Anne;Olszewska,Malgorzata;Xiao,Tong;Abramowicz,Sandra;Papapetrou,EiriniP;Westerterp,Marit;Wang,Nan;Tabas,Ira;Tall,AlanR
通讯作者：
Tall,AlanR

Pegylation of high-density lipoprotein decreases plasma clearance and enhances antiatherogenic activity.

DOI：
10.1161/circresaha.113.301112
发表时间：
2013-06-21
期刊：
Circulation research
影响因子：
20.1
作者：
Murphy AJ;Funt S;Gorman D;Tall AR;Wang N
通讯作者：
Wang N

ABCA1 Exerts Tumor-Suppressor Function in Myeloproliferative Neoplasms.

ABCA1 在骨髓增生性肿瘤中发挥肿瘤抑制功能。

DOI：
10.1016/j.celrep.2020.02.056
发表时间：
2020
期刊：
Cell reports
影响因子：
8.8
作者：
Viaud,Manon;Abdel-Wahab,Omar;Gall,Julie;Ivanov,Stoyan;Guinamard,Rodolphe;Sore,Sophie;Merlin,Johanna;Ayrault,Marion;Guilbaud,Emma;Jacquel,Arnaud;Auberger,Patrick;Wang,Nan;Levine,RossL;Tall,AlanR;Yvan-Charvet,Laurent
通讯作者：
Yvan-Charvet,Laurent

Cholesterol, inflammation and innate immunity.