The role of mitochondrial CaMKII in diabetic vascular restenosis

线粒体CaMKII在糖尿病血管再狭窄中的作用

基本信息

批准号：
9044393
负责人：
Emily Kim Nguyen
金额：
$ 2.9万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-15 至 2019-08-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9044393
关键词：
Attenuated Blood Vessels Calcium Calmodulin Cardiovascular system Carotid Arteries Cause of Death Citric Acid Cycle Coronary Data Development Diabetes Mellitus Diabetic Angiopathies Disease Electron Transport Figs - dietary Fostering Future Goals Health Hyperglycemia Hyperplasia Injury Intervention Knowledge Lead Mediating Mediator of activation protein Medicine Metabolic Metabolism Mission Mitochondria Molecular Morphology Mus Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Oxidative Phosphorylation Oxidative Stress Oxidoreductase Patients Peripheral Pharmaceutical Preparations Phosphotransferases Population Procedures Production Public Health Reactive Oxygen Species Research Respiration Risk Role Severities Signal Transduction Smooth Muscle Myocytes Stents Stroke Techniques Testing Therapeutic Transgenic Mice Transgenic Model Tricarboxylic Acids Vascular Smooth Muscle base calmodulin-dependent protein kinase II diabetic diabetic patient effective therapy feeding glycosylation improved in vivo in vivo Model inhibitor/antagonist injured migration mitochondrial metabolism mouse model new therapeutic target novel overexpression pre-doctoral prevent public health relevance research study response restenosis therapeutic development uptake vascular smooth muscle cell migration vascular smooth muscle cell proliferation

项目摘要

DESCRIPTION (provided by applicant): Over half a million coronary interventions are performed every year in the US. However, the growing population of diabetic patients have a 30% increased risk of restenosis due to neointimal hyperplasia after coronary intervention, demonstrating that effective treatment for diabetic patients remains a major issue in cardiovascular medicine. A major contributor to diabetic vascular disease is mitochondrial reactive oxygen species (mtROS), due to an excess of metabolic substrates and overload of mitochondrial respiration. Recently, Ca2+/calmodulin dependent protein kinase II (CaMKII) was found in mitochondria, where it signals through mitochondrial Ca2+ uniporter (MCU) to increase Ca2+ entry into mitochondria. Ca2+ influx into mitochondria is known to drive metabolism through the Krebs cycle and the electron transport chain. Sustained mtROS elevations lead to global ROS increases, which promote vascular smooth muscle cell (VSMC) proliferation, a major contributor to neointimal hyperplasia. The objective of my application is to determine how CaMKII in VSMC regulates mitochondrial metabolism and ROS production in diabetes and directly test whether its inhibition in mitochondria abrogates neointimal hyperplasia in diabetes in vivo. I hypothesize that mitochondrial CaMKII promotes neointimal hyperplasia in diabetes through increased mitochondrial ROS production resulting from ineffective metabolic activity. To test this hypothesis, I will utilize an in vivo model of diabetes in mice with VSMC-specific mitochondrial CaMKII inhibition (mtCaMKIIN mice) to discover if they have less mtROS, less mitochondrial Ca2+ loading and protection from neointimal hyperplasia. I will also dissect the mechanism for mtCaMKII's role in mitochondrial metabolism of VSMC, using cutting edge techniques to assess metabolic activity. My studies will test the hypothesis through two specific aims: 1) test whether mtCaMKII inhibition reduces neointimal hyperplasia in diabetes mellitus; 2) determine the mechanisms by which mtCaMKII controls mtROS production and metabolic activity. These studies will establish how mitochondrial CaMKII and mitochondrial Ca2+ contribute to mtROS production in diabetic restenosis and to determine whether these represent viable targets for future therapeutic development.

描述（由适用提供）：在美国，每年进行超过半百万的冠状动脉干预措施。然而，由于冠状动脉介入后，由于新内膜增生而增加的糖尿病患者人群增加了30％的再狭窄风险，这表明对糖尿病患者的有效治疗仍然是心血管医学的主要问题。糖尿病血管疾病的主要因素是线粒体活性氧（MTROS），这是由于代谢底物过多和线粒体呼吸的过载。最近，在线粒体中发现了Ca2+/钙调蛋白依赖性蛋白激酶II（CAMKII），在那里它通过线粒体Ca2+ Uniter（MCU）发出信号，以增加Ca2+进入线粒体的进入。已知Ca2+对线粒体的影响会通过克雷布斯循环和电子传输链驱动代谢。持续的MTROS升高导致全球ROS增加，从而促进血管平滑肌细胞（VSMC）增殖，这是新肾上腺素增生的主要原因。我应用的目的是确定VSMC中的CAMKII如何调节糖尿病中的线粒体代谢和ROS产生，并直接测试其在线粒体中的抑制作用是否消除了体内糖尿病中的新蛋白含量增生。我假设线粒体CAMKII通过无效的代谢活性导致的线粒体ROS产生增加了糖尿病中的新肾上腺素增生。为了检验这一假设，我将利用VSMC特异性线粒体CAMKII抑制（MTCAMKIIN小鼠）的小鼠中的糖尿病体内模型，以发现它们是否具有较小的MTRO，较少的线粒体Ca2+负载和免受新质蛋白质超质体的载荷和保护。我还将使用尖端技术来评估新陈代谢活性的MTCAMKII在VSMC的线粒体代谢中的作用。我的研究将通过两个特定目的检验假设：1）测试mtCAMKII抑制是否会减少糖尿病中的新内膜增生； 2）确定MTCAMKII控制MTROS产生和代谢活性的机制。这些研究将确定线粒体CAMKII和线粒体Ca2+如何促进糖尿病再狭窄中的MTROS产生，并确定这些糖是对未来治疗性发育的可行靶标。