Cholesterol efflux, CHIP and inflammasome activation

项目摘要/摘要 动脉粥样硬化性心血管疾病仍然是#年发病率和死亡率的主要原因。 美国。尽管降低低密度脂蛋白疗法有好处，但仍有很大的残留负担。 心血管疾病，与持续性血脂异常和炎症有关。即使是《诗篇》和《秋水仙》 试验已经证实了抗炎疗法的好处，这些方法是 相关的感染性并发症显著增加，限制了其临床应用。 这表明有必要更深入地了解血脂异常和高血压之间的联系。 动脉粥样硬化性炎症，导致更有效的靶向相关机制和 易感人群。这笔赠款支持了对缺陷连接机制的研究。 胆固醇外流到巨噬细胞和中性粒细胞炎症过程的途径，包括 NLRP3炎性小体激活，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聚的新途径(通过 有缺陷的胆固醇外流或负载修饰的低密度脂蛋白)导致内质网胆固醇蓄积 激活导致NLRP3去泛素化和组装的信号通路 炎症者。用去泛素酶抑制剂霍尔霉素抑制这一途径可导致 减少动脉粥样硬化和网状血管病变，提出了一种减少炎性小体的新方法 活化和动脉粥样硬化。同样的途径似乎在TET2克隆中被激活 造血术。拟议的研究将进一步探索新定义的途径的作用 对高脂血症小鼠NLRP3炎性小体激活和动脉粥样硬化的促进作用 有缺陷的胆固醇外流或TET2克隆性造血和含有TET2的人细胞 突变。重组高密度脂蛋白促进和逆转胆固醇外流的能力 还将调查导致斑块稳定的炎性小体激活。这项建议 应该为巨噬细胞胆固醇之间的联系提供新的机械见解 积聚和斑块炎症，并将评估新的精确治疗方法 致动脉粥样硬化。

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.