Mechanisms of Atherogenesis in Insulin Resistance

描述（由申请人提供）： 胰岛素抵抗、代谢综合征和2型糖尿病的发病率由于工业化国家的肥胖流行而迅速上升。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血栓形成性心血管疾病。然而，胰岛素抵抗与动脉粥样硬化血栓形成之间的分子和细胞机制知之甚少，部分原因是这一领域福尔斯两个不同的研究领域之间。拟议的PPG将汇集这些不同领域的专家，以阐明有助于胰岛素抵抗加速动脉粥样硬化的新信号转导途径。PPG集中于该竞技场中的两个关键过程：（1）晚期动脉粥样硬化中巨噬细胞（Mfs）的死亡，其在胰岛素抵抗中加速并产生易损斑块的坏死核心;和（2）致动脉粥样硬化脂蛋白的肝脏产生，其在胰岛素抵抗中受到干扰并导致血脂异常。每个项目都基于PPG研究者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一种新的，多击中促凋亡信号通路在Mfs，这是促进Mf胰岛素抵抗本身和全身胰岛素抵抗通过减少脂联素，脂肪细胞因子，塔巴斯实验室发现抑制Mfs细胞凋亡信号。在项目2中，Tall博士与项目1和3合作，将研究Mf胰岛素抵抗和下游凋亡效应子之间的分子联系，重点是Akt和FoxO信号传导。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致动脉粥样硬化性血脂异常，重点是FoxO 1的转录调控。Accili博士还将与塔巴斯和Tall博士合作，研究FoxO作为Mfs细胞凋亡信号传导介质的作用。每个项目都将得到病变分析/生物统计学核心的支持，Welch博士的团队将在小鼠动脉粥样硬化测定和生物数学方面提供帮助和专业知识。这些项目的协同作用和高度互动性以及PPG研究人员在动脉粥样硬化和胰岛素信号传导方面的互补专业知识将为解决胰岛素抵抗相关心脏病的新流行提供独特的机会。

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.