Cellular and molecular mechanisms of diabetic atherosclerosis

项目摘要/摘要 动脉粥样硬化引起的心血管疾病(CVD)是世界范围内主要的死亡原因。 由于肥胖、胰岛素抵抗和2型糖尿病的日益流行，预防心血管疾病的进展陷入停滞 糖尿病(T2D)，它增加了发生动脉粥样硬化性血管疾病的相对风险 并发症是非糖尿病患者的四倍。尽管如此，细胞和分子 糖尿病动脉粥样硬化的发病机制尚不清楚，适当的治疗策略也不清楚。 用于预防和治疗糖尿病患者的心血管疾病。我们最近开发了一种口服用药， 促进肝脏氧化的肝脏定向控制释放线粒体原载体(CRMP) 甘油三酯通过促进肝脏线粒体效率的微妙持续增加而显示出这一点 该药可安全逆转啮齿类动物的高甘油三酯血症、脂肪肝、胰岛素抵抗和肝纤维化 肥胖的非人类灵长类动物模型。在这里，我们将利用CRMP的胰岛素增敏作用直接 用小鼠模型评估高胰岛素血症和胰岛素抵抗在糖尿病动脉粥样硬化形成中的作用 代谢综合征(目标1和2)。我们假设慢性CRMP治疗会降低肝脏 肝脏线粒体脂肪氧化率增加引起的脂肪变性、胰岛素抵抗和血脂异常， 这反过来又会降低动脉粥样硬化的易感性。此外，我们还将开发和利用新的状态- 应用-ART代谢示踪法研究巨噬细胞免疫代谢的调节 糖尿病动脉粥样硬化(AIM 3)，作为炎症状态与生物能量谱之间的关系 体内斑块巨噬细胞及其对动脉粥样硬化发展和稳定性的影响在很大程度上仍然存在。 未知。我们假设肥胖和T2D将增加葡萄糖的供应和利用 巨噬细胞将启动前馈循环，促进炎症并进一步加重 总而言之，这项工作将为调控糖尿病的机制提供有意义的见解 动脉粥样硬化，对于了解肝脏线粒体的治疗作用至关重要 治疗心脏代谢性疾病的解偶联药物。因此，我们提出了一个专注的职业生涯 发展培训计划，在此期间，申请者将接受负责任的研究行为培训； 学习动脉粥样硬化斑块切片和表征的各个方面；开发和利用 评估巨噬细胞免疫代谢的稳定同位素方法；以及大数据的生物信息学分析 布景。这项工作将在候选人的主要导师Gerald Shulman博士的监督下进行， 导师威廉·塞萨博士、合作者卡洛斯·费尔南德斯·埃尔南多博士和蕾切尔·佩里。通过 完成本申请表(K99)中建议的培训后，申请人将获得知识和 将为她提供在后续阶段(R00)实现科学自主的初步步骤的技能 成功地从博士后实习生角色过渡到独立研究人员角色。

PROJECT SUMMARY/ABSTRACT Cardiovascular disease (CVD) due to atherosclerosis represents the leading cause of death worldwide. Progress in preventing CVD has been stalled by the growing epidemic of obesity, insulin resistance and type 2 diabetes (T2D), which increases the relative risk of developing atherosclerotic vascular disease and its complications four-fold compared to non-diabetic individuals. Despite this, the cellular and molecular mechanisms underlying the incidence of diabetic atherosclerosis are still unclear, as are appropriate strategies for the prevention and treatment of CVD in diabetic patients. We have recently developed an orally available, liver-directed controlled release mitochondrial protonophore (CRMP) that promotes oxidation of hepatic triglycerides by promoting a subtle sustained increase in hepatic mitochondrial inefficiency and shown that this agent safely reverses hypertriglyceridemia, fatty liver, insulin resistance and liver fibrosis in rodent and nonhuman primate models of obesity. Here, we will leverage the insulin-sensitizing effects of CRMP to directly assess the role of hyperinsulinemia and insulin resistance in driving diabetic atherosclerosis in a murine model of metabolic syndrome (Aims 1 and 2). We hypothesize that chronic CRMP treatment will reduce hepatic steatosis, insulin resistance and dyslipidemia due to increases in rates of hepatic mitochondrial fat oxidation, which in turn will reduce susceptibility to atherosclerosis. In addition, we will develop and utilize novel state-of- the-art metabolic tracer methods to characterize the regulation of macrophage immunometabolism during diabetic atherosclerosis (Aim 3), as the relationship between the inflammatory status and bioenergetic profile of plaque macrophages in vivo, as well as its impact on atherosclerotic development and stability, remains largely unknown. We hypothesize that obesity and T2D will increase glucose availability and utilization in macrophages which will initiate a feed forward loop that fosters inflammation and further aggravates atherosclerosis Collectively, this work will provide meaningful insight into the mechanisms regulating diabetic atherosclerosis and will be critical for understanding the therapeutic utility of liver-directed mitochondrial uncoupling agents for the treatment of cardiometabolic diseases. Therefore, we propose a focused career development training plan during which the applicant will be trained in the responsible conduct of research, learning all aspects of atherosclerotic plaque sectioning and characterization; the development and utilization of stable isotope methods to assess macrophage immunometabolism; and bioinformatics analysis of large data sets. This will be carried out under the supervision of the candidate’s primary mentor Dr. Gerald Shulman, co- mentor Dr. William Sessa, and collaborators Drs. Carlos Fernandez-Hernando and Rachel Perry. By completing the proposed training outlined in this application (K99), the applicant will obtain the knowledge and skills that will provide her with the initial steps towards scientific autonomy in the subsequent phase (R00) and transition successfully from the role of postdoctoral trainee to that of an independent researcher.