Role of Immune Mechanisms in Athersclerosis and Inflammation

动脉粥样硬化现在被认为是一种慢性炎症性疾病，我们PPG的项目负责人为人们广泛认识到免疫机制在调节动脉粥样硬化形成中发挥核心作用做出了开创性的信息。利用在第一个周期中获得的信息，我们建议研究巨噬细胞、T细胞、B细胞、天然抗体(NAB)和天然TLRs在炎症和动脉粥样硬化形成中的作用。项目1将继续他们的开创性观察，即胆固醇喂养的小鼠腹膜中泡沫细胞的形成表现出一种意想不到的抑制炎症基因表型，这是由于LXR的一种有效配体Desmosterol的积累，导致了炎症基因表达的抑制。他们将研究这种情况发生的转录机制，并确定是否可以基于使用抑制炎症活动的Desmosterol样剂来开发新的治疗方法。项目2将继续他们的发现，即PPARy是用Treg表达的 主动脉周围脂肪组织中的细胞，位于动脉粥样硬化增强的关键解剖部位的主动脉周围。他们将探索一种假设，即这是由促炎症基因网络介导的，该网络可以在转录水平上受到PPARy和REVERBA/p的调节，调节Treg和Th17细胞的重要功能。项目3将继续他们最近发现的氧化特定表位(OSE)，就像发生在OxLDL或凋亡细胞上的那样，是先天NAB的主要目标。他们将专注于定义OSE-nabs在人类和小鼠中的流行率，它们具有动脉粥样硬化保护作用的机制，并定义GR和LXR调节B-1细胞的转录机制，B-1细胞产生nabs。总体而言，这些研究应该为适应性免疫和先天免疫调节炎症和动脉粥样硬化的新机制提供重要的见解，并可能导致心血管疾病的新诊断和治疗方法。

Atherosclerosis is now recognized as a chronic inflammatory disease, and Project Leaders of our PPG have contributed seminal information to the widespread recognition that immune mechanisms play a central role in modulating atherogenesis. Leveraging information gained in the first cycle, we propose studies of the roles of macrophages, T cells, B cells, Natural antibodies (NAbs) and innate TLRs on inflammation and atherogenesis. Project 1 will pursue their seminal observations that foam cell formation in the peritoneum of cholesterol-fed mice exhibited an unexpected suppressed inflammatory gene phenotype, which was due to accumulation of desmosterol, a potent LXR ligand, leading to inhibition of inflammatory gene expression. They will study the transcriptional mechanisms by which this occurs, and determine if novel therapeutic approaches can be exploited based on use of desmosterol-like agents that inhibit inflammatory activity. Project 2 will pursue their findings that PPARy is expressed in Treg cells in peri-aortic adipose tissue, which surrounds the aorta at key anatomical sites where atherogenesis is enhanced. They will explore the hypothesis that this is mediated by a proinflammatory gene network that can be modulated at the transcriptional level by PPARy and REVERBa/p, regulating vital functions of Treg and Th17 cells. Project 3 will pursue their recent identification that oxidation specific epitopes (OSE), as occur on OxLDL or apoptotic cells, are major targets of innate NAbs. They will focus on defining the prevalence of OSE-NAbs in humans and mice, the mechanisms by which they are atheroprotective, and define transcriptional mechanisms by which GR and LXR regulate B-1 cells, which generate NAbs. Overall, these studies should provide vital insights into novel and as yet unexplored mechanisms by which adaptive and innate immunity regulates inflammation and atherosclerosis, and may lead to novel diagnostic and therapeutic approaches for cardiovascular disease.