Cellular and molecular mechanisms of diabetic atherosclerosis

糖尿病动脉粥样硬化的细胞和分子机制

基本信息

批准号：
10556834
负责人：
Leigh Goedeke
金额：
$ 24.9万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10556834
关键词：
Address Affect Animal Model Antidiabetic Drugs Arterial Fatty Streak Atherosclerosis Attenuated Automobile Driving Bioenergetics Bioinformatics Cardiometabolic Disease Cardiovascular Diseases Cause of Death Cells Cholesterol Chronic Data Development Dyslipidemias Fatty Liver Fatty acid glycerol esters Fostering Glucose Glycolysis Hepatic High Fat Diet Hyperglycemia Hyperinsulinism Hypertriglyceridemia Immune Incidence Individual Inflammation Inflammatory Insulin Insulin Resistance Knowledge Learning Lesion Link Lipids Liver Liver Fibrosis Liver Mitochondria Measures Mentors Metabolic Metabolic syndrome Metabolism Methods Mitochondria Modeling Molecular Morbidity - disease rate Mus Non-Insulin-Dependent Diabetes Mellitus Obesity Obesity Epidemic Oral Phase Plasma Play Predisposition Prevention strategy Publishing Regulation Relative Risks Research Research Personnel Risk Risk Factors Rodent Rodent Model Role Rupture Supervision Therapeutic Time Tracer Training Triglycerides Tumor-infiltrating immune cells Uncoupling Agents Work atherogenesis cardiovascular disorder risk career development controlled release diabetic diabetic patient diet-induced obesity fat burning fatty acid oxidation gene therapy hypercholesterolemia in vivo insight insulin sensitivity insulin sensitizing drugs large datasets macrophage metabolic profile mortality mouse model non-alcoholic fatty liver disease non-diabetic nonalcoholic steatohepatitis nonhuman primate novel novel therapeutics oxidation prevent responsible research conduct skills stable isotope western diet

项目摘要

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.

项目概要/摘要动脉粥样硬化引起的心血管疾病（CVD）是全世界死亡的主要原因。由于肥胖、胰岛素抵抗和 2 型糖尿病的日益流行，预防 CVD 的进展已陷入停滞糖尿病（T2D），它增加了患动脉粥样硬化性血管疾病的相对风险及其尽管如此，细胞和分子方面的并发症却是非糖尿病个体的四倍。糖尿病动脉粥样硬化发病的机制尚不清楚，适当的策略也不清楚我们最近开发了一种口服药物，用于预防和治疗糖尿病患者的心血管疾病。肝脏定向控释线粒体质子载体（CRMP），促进肝脏氧化通过促进肝线粒体效率的微妙持续增加来降低甘油三酯，并表明这该药物可安全逆转啮齿动物和动物的高甘油三酯血症、脂肪肝、胰岛素抵抗和肝纤维化在这里，我们将利用 CRMP 的胰岛素增敏作用来直接研究肥胖的非人类灵长类动物模型。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我们发现长期 CRMP 治疗会降低肝脏的代谢综合征（目标 1 和 2）。由于肝线粒体脂肪氧化速率增加导致脂肪变性、胰岛素抵抗和血脂异常，这反过来将降低动脉粥样硬化的易感性。此外，我们将开发和利用新的状态。最先进的代谢示踪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（目标 3），炎症状态与生物能特征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仍然在很大程度上我们探索肥胖和 T2D 会增加葡萄糖的可用性和利用率。巨噬细胞将启动前馈循环，促进炎症并进一步加剧总的来说，这项工作将为调节糖尿病的机制提供有意义的见解动脉粥样硬化，对于理解肝脏定向线粒体的治疗效用至关重要因此，我们建议专注于治疗心脏代谢疾病的解偶联剂。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；稳定同位素方法评估巨噬细胞免疫代谢和大数据生物信息学分析；这将在候选人的主要导师 Gerald Shulman 博士（共同）的监督下进行。 William Sessa 博士及其合作者指导 Carlos Fernandez-Hernando 博士和 Rachel Perry 博士。完成本申请（K99）中概述的拟议培训后，申请人将获得知识和这些技能将为她在后续阶段（R00）提供迈向科学自主的初步步骤，以及成功从博士后实习生角色转变为独立研究员角色。