Mechanisms of Atherogenesis in Insulin Resistance

描述(由申请人提供)： 由于工业化世界的肥胖流行，胰岛素抵抗、代谢综合征和2型糖尿病的发病率正在迅速上升。胰岛素抵抗的发病率和死亡率的主要原因是动脉粥样硬化性血栓心血管病。然而，将胰岛素抵抗与动脉粥样硬化血栓形成联系起来的分子和细胞机制知之甚少，部分原因是这一领域处于两个不同的研究领域之间。拟议的PPG将把这些不同领域的专家聚集在一起，阐明导致胰岛素抵抗中动脉粥样硬化加速的新的信号转导途径。PPG专注于这一领域的两个关键过程：(1)晚期动脉粥样硬化中巨噬细胞(MFS)的死亡，这在胰岛素抵抗中加速，并导致脆弱斑块的坏死核心；(2)肝脏产生致动脉粥样硬化的脂蛋白，这在胰岛素抵抗中受到干扰，并导致血脂异常。每个项目都是基于PPG调查人员合作获得的关键机制和体内数据。在项目1中，塔巴斯博士将专注于MFS中一种新颖的、多靶点的促凋亡信号通路，该信号通路既由MF胰岛素抵抗本身促进，也由全身性胰岛素抵抗通过脂联素的减少促进。脂联素是Tabas实验室发现的一种抑制MFS中的凋亡信号的脂肪细胞因子。在项目2中，Tall博士将与项目1和项目3合作，研究MF胰岛素抵抗和下游细胞凋亡效应之间的分子联系，重点是Akt和FoxO信号转导。项目2还将通过研究选择性肝脏胰岛素敏感性如何预防致动脉粥样硬化性血脂异常的分子机制来补充项目3中的研究。在项目3中，Accili博士将与Tall博士合作，研究选择性肝脏胰岛素抵抗如何导致动脉粥样硬化性血脂异常，重点是FoxO1的转录调控。Accili博士还将与Tabas博士和Tall博士合作，研究FoxO在MFS中作为凋亡信号介体的作用。每个项目都将得到损伤分析/生物统计核心的支持，韦尔奇博士的团队将在小鼠动脉粥样硬化分析和生物数学方面提供帮助和专业知识。这些项目的协作性和高度互动性，以及PPG研究人员在动脉粥样硬化和胰岛素信号方面的互补专业知识，将使我们有机会解决与胰岛素抵抗相关的心脏病这一新出现的流行病。

DESCRIPTION (provided by applicant): The incidence of insulin resistance, metabolic syndrome, and type 2 diabetes is rising rapidly due to the obesity epidemic in the industrialized world. The leading cause of morbidity and mortality in insulin resistance is atherothrombotic cardiovascular disease. However, the molecular and cellular mechanisms linking insulin resistance to atherothrombosis are poorly understood, in part because this area falls between two distinct fields of research. The proposed PPG will bring together experts in these different areas to elucidate novel signal transduction pathways that contribute to accelerated atherosclerosis in insulin resistance. The PPG focuses on two key processes in this arena: (1) death of macrophages (Mfs) in advanced atherosclerosis, which is accelerated in insulin resistance and gives rise to the necrotic core of vulnerable plaques; and (2) hepatic production of atherogenic lipoproteins, which is perturbed in insulin resistance and leads to dyslipidemia. Each project is based on key mechanistic and in-vivo data obtained collaboratively by the PPG investigators. In Project 1, Dr. Tabas will focus on a novel, multi-hit pro-apoptotic signaling pathway in Mfs that is promoted by both Mf insulin resistance itself and by systemic insulin resistance through reduction in adiponectin, an adipocytokine that the Tabas lab found suppresses apoptosis signaling in Mfs. In Project 2, Dr. Tall, in collaboration with Projects 1 and 3, will investigate the molecular connections between Mf insulin resistance and downstream apoptosis effectors, with a focus on Akt and FoxO signaling. Project 2 will also complement the studies in Project 3 by studying the molecular mechanisms of how selective hepatic insulin sensitivity prevents atherogenic dyslipidemia. In Project 3, Dr. Accili will work with Dr. Tall to study how selective hepatic insulin resistance leads to atherogenic dyslipidemia, with a focus on transcriptional regulation by FoxO1. Dr. Accili will also collaborate with Drs. Tabas and Tall to investigate the role of FoxO as a mediator of apoptosis signaling in Mfs. Each project will be supported by the Lesion Analysis/ Biostatistics Core, in which Dr. Welch's team will provide assistance and expertise in mouse atherosclerosis assays and in biomathematics. The synergistic and highly interactive nature of these projects and the complementary expertise in atherosclerosis and insulin signaling among the PPG investigators will enable a unique opportunity to address the emerging epidemic of insulin resistance-associated heart disease.