Cellular and molecular mechanisms of diabetic atherosclerosis

项目总结/摘要 由动脉粥样硬化引起的心血管疾病（CVD）是全球死亡的主要原因。 由于肥胖、胰岛素抵抗和2型糖尿病的流行， 糖尿病（T2D），其增加了发展动脉粥样硬化性血管疾病的相对风险， 与非糖尿病患者相比，其并发症增加了四倍。尽管如此，细胞和分子 糖尿病动脉粥样硬化发生的机制尚不清楚，适当的治疗策略也不清楚 用于预防和治疗糖尿病患者的CVD。我们最近开发了一种口服的， 肝定向控释线粒体质子载体（CRMP），促进肝细胞氧化 甘油三酯通过促进肝脏线粒体效率低下的微妙持续增加，并表明这 药物可安全逆转啮齿类动物的高脂血症、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， 评估高胰岛素血症和胰岛素抵抗在小鼠模型中驱动糖尿病动脉粥样硬化的作用 代谢综合征（目标1和2）。我们假设慢性CRMP治疗将减少肝脏的 由于肝线粒体脂肪氧化速率增加导致的脂肪变性、胰岛素抵抗和血脂异常， 这反过来将降低对动脉粥样硬化的易感性。此外，我们将开发和利用新的国家， 现有技术的代谢示踪剂方法来表征巨噬细胞免疫代谢的调节， 糖尿病动脉粥样硬化（目的3），作为炎症状态和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， 未知我们假设肥胖和2型糖尿病会增加糖尿病患者的葡萄糖可用性和利用率， 巨噬细胞，这将启动前馈循环，促进炎症，并进一步 总的来说，这项工作将提供有意义的洞察机制调节糖尿病 动脉粥样硬化，并将是至关重要的了解肝定向线粒体的治疗效用， 用于治疗心脏代谢疾病的解偶联剂。因此，我们建议专注于职业 制定培训计划，在此期间，申请人将接受负责任的研究行为培训， 了解动脉粥样硬化斑块切片和表征的各个方面;开发和利用 稳定同位素方法评估巨噬细胞免疫代谢;以及大数据的生物信息学分析 集.这将在候选人的主要导师Gerald Shulman博士的监督下进行， 导师William Sessa博士和合作者卡洛斯费尔南德斯-埃尔南多博士和雷切尔佩里博士。通过 完成本申请（K99）中概述的拟议培训后，申请人将获得知识， 这些技能将为她在随后的阶段（R00）中实现科学自主提供初步步骤， 成功地从博士后实习生的角色过渡到独立研究者的角色。

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.