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.

项目摘要/摘要由于动脉粥样硬化而引起的心血管疾病（CVD）代表了全球死亡的主要原因。预防CVD的进展已被肥胖，胰岛素抵抗和2型的越来越多的流行病所阻止糖尿病（T2D），增加了发生动脉粥样硬化血管疾病及其的相对风险与非糖尿病个体相比，并发症四倍。尽管如此，细胞和分子糖尿病动脉粥样硬化事件的基础机制仍然不清楚，适当的策略也尚不清楚用于预防和治疗糖尿病患者的CVD。我们最近开发了一个口服，肝导向的受控释放线粒体质子团（CRMP）促进肝的氧化甘油三酸酯通过促进肝线粒体无效的微妙持续增加，并表明这一点剂安全地逆转高甘油三酸酯血症，脂肪肝，胰岛素抵抗和肝纤维化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的胰岛素敏感作用直接评估高胰岛素血症和胰岛素抵抗在鼠模型中驱动糖尿病动脉粥样硬化中的作用代谢综合征（目标1和2）。我们假设慢性CRMP治疗将减少肝脂肪变性，胰岛素抵抗和血脂异常，这是由于肝线粒体脂肪氧化速率增加而导致的这反过来将减少对动脉粥样硬化的敏感性。此外，我们将开发和利用新颖的最新 ART代谢示踪剂方法是表征巨噬细胞免疫代谢过程中的调节的方法糖尿病动脉粥样硬化（AIM 3），作为炎症状况与生物能谱之间的关系体内斑块巨噬细胞及其对动脉粥样硬化发育和稳定性的影响在很大程度上仍然是未知。我们假设肥胖和T2D会增加葡萄糖的可用性和利用率巨噬细胞将启动饲料向前循环，以促进注射并进一步加剧动脉粥样硬化，这项工作将提供对调节糖尿病机制的有意义的见解动脉粥样硬化，对于理解实时线粒体的治疗效用至关重要用于治疗心脏代谢疾病的解偶联剂。因此，我们提出了一个专注的职业开发培训计划，在此期间，申请人将接受负责任的研究进行培训，学习动脉粥样硬化斑块切片和特征的所有方面；开发和利用评估巨噬细胞免疫代谢的稳定同位素方法；和大数据的生物信息学分析套。这将在候选人的主要导师杰拉尔德·舒尔曼（Gerald Shulman）博士的监督下进行。导师威廉·塞萨（William Sessa）博士和合作者博士。 Carlos Fernandez-Hernando和Rachel Perry。经过完成本申请中概述的拟议培训（K99），该应用程序将获得知识和在随后的阶段（R00）和从博士后学员的角色成功过渡到独立研究人员的角色。