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的项目负责人贡献了开创性的信息，使人们广泛认识到免疫机制在调节动脉粥样硬化发生中起着核心作用。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）和先天tlr在炎症和动脉粥样硬化中的作用。项目1将继续他们的种子观察，即胆固醇喂养小鼠腹膜中的泡沫细胞形成表现出意想不到的抑制炎症基因表型，这是由于去氨甾醇（一种有效的LXR配体）的积累导致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，并确定是否可以利用抑制炎症活性的去氨甾醇样药物来开发新的治疗方法。项目2将继续他们的发现，即pparty是用Treg表达的

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.