Mechanisms of Atherogenesis in Insulin Resistance

描述(申请人提供)：肥胖的流行导致胰岛素抵抗及其主要并发症--动脉粥样硬化性心血管疾病(CVD)的发生率急剧上升。因此，了解胰岛素抵抗在触发和维持动脉粥样硬化的肝脏血脂异常中的作用，以及在斑块细胞本身发生的致动脉粥样硬化事件中所起的作用，是非常有兴趣的。拟议的PPG将把这些不同领域的专家聚集在一起，努力实现一个共同的目标，并在过去5年的资助中取得了公认的成功记录。PPG的总体主题是阐明肝脏、病变巨噬细胞(MFS)和内皮细胞(ECs)中导致胰岛素抵抗状态下血脂异常和动脉粥样硬化病变加速进展的新的信号转导途径。在项目1中，塔巴斯博士将重点研究CaMKII酶，它在(A)基础和胰岛素抵抗加剧中都起着关键作用 内质网(ER)应激的MFS的凋亡，导致斑块坏死；以及(B)肝脏衍生的代谢紊乱，包括血脂异常和FoxO信号的改变，与肥胖和胰岛素抵抗有关。在项目2中，Tall博士将研究胰岛素抵抗中肝源性血脂异常的细胞-分子机制，重点是与最近的人类遗传学研究相关的新的mTORC1-Sortilin1途径，以及最近的数据显示与内质网应激和CaMKII有关的途径。在项目3中，Accili博士将重点研究血管内皮细胞作为胰岛素抵抗和高血糖在动脉粥样硬化中相互作用的关键部位。重点将放在胰岛素抵抗和高血糖如何通过FoxO蛋白发出信号来促进内皮细胞的动脉粥样硬化过程。每个项目都将得到病变分析/生物统计核心的支持，韦尔奇博士的团队将在动脉粥样硬化分析和生物数学方面提供援助和专业知识。这些项目中的共同子主题包括：(A)参与促动脉粥样硬化的损害细胞功能障碍(MFS，ECs)的分子和途径，包括FoxO、ER Stress、CaMKII、mTORC1(所有3个项目)；(B)涉及胰岛素抵抗引起的血脂异常的途径，包括FoxO、ER Stress、mTORC1、Sortilin1和CaMKII(与Accili博士合作的项目1和2)；(C)动脉粥样硬化病变发展和晚期斑块进展/斑块坏死的小鼠模型(所有3个项目和核心A)。这些项目的协同性和高度互动性，以及动脉粥样硬化和糖尿病方面的互补专业知识，将为解决与胰岛素抵抗相关的心脏病的新流行提供一个独特的机会。

DESCRIPTION (provided by applicant): The epidemic of obesity is causing a sharp rise in the incidence of insulin resistance and its major complication, atherosclerotic cardiovascular disease (CVD). Thus, there is great interest in understanding the role of insulin resistance in both hepatic dyslipidemia, which triggers and maintains atherosclerosis, and in atherogenic events occurring in the plaque cells themselves. The proposed PPG will bring together experts in these different areas working towards a common goal and with a proven record of success over the last 5 years of funding. The overall theme of the PPG is to elucidate novel signal transduction pathways in the liver and in lesional macrophages (Mfs) and endothelial cells (ECs) that contribute to the dyslipidemia and accelerated atherosclerotic lesion progression in insulin-resistant states. In Project 1, Dr. Tabas will focus on the enzyme CaMKII, which has a critical role in (a) both basal and insulin resistance-exacerbated apoptosis of endoplasmic reticulum (ER)-stressed Mfs, which leads to plaque necrosis; and (b) in hepatic derived metabolic disturbances, including dyslipidemia and alterations in FoxO signaling, in obesity and insulin resistance. In Project 2, Dr. Tall will investigate the cellular-molecular mechanisms of hepatic-derived dyslipidemia in insulin resistance, with, emphasis on a novel mTORC1-Sortilin1 pathway that is relevant to recent human genetic studies and, as recent data shows, linked to ER stress and CaMKII. In Project 3, Dr. Accili will focus on vascular ECs as a key site of interaction between insulin resistance and hyperglycemia in atherosclerosis. The emphasis will be on how insulin resistance and hyperglycemia signal through the FoxO proteins to promote atherogenic processes in ECs. Each project will be supported by the Lesion Analysis/Biostatistics Core, in which Dr. Welch's team will provide assistance and expertise in atherosclerosis assays and in biomathematics. The common sub-themes among the projects include: (a) molecules and pathways involved in pro-atherogenic lesional cell dysfunction (Mfs, ECs), including FoxO's, ER stress, CaMKII, mTORC1 (all 3 projects); (b) pathways involved insulin resistance-induced dyslipidemia, including FoxO's, ER stress, mTORC1, Sortilin1, and CaMKII (Projects 1 and 2 in collaboration with Dr. Accili); and (c) mouse models of atherosclerotic lesion development and advanced plaque progression/plaque necrosis (all 3 projects and Core A). The synergistic and highly interactive nature of these projects and the complementary expertise in atherosclerosis and diabetes will enable a unique opportunity to address the emerging epidemic of insulin resistance-associated heart disease.