Importance of Mitochondria in the Endothelial Dysfunction of Type 2 Diabetes

线粒体在 2 型糖尿病内皮功能障碍中的重要性

基本信息

批准号：
8289549
负责人：
Michael E Widlansky
金额：
$ 13.54万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8289549
关键词：
Acceleration Accounting Adipose tissue Atherosclerosis Bioavailable Biogenesis Bioinformatics Biological Availability Biology Biopsy Blood Vessels Cardiovascular system Cells Cessation of life Chronic Collaborations Coronary Data Development Development Plans Diabetes Mellitus Diabetic Angiopathies Disease Dose Endothelial Cells Endothelium Enzymes Event Exposure to Feedback Functional disorder Future Gene Expression Gene Expression Profile Generations Genes Genetic Research Genetic Transcription Genomics Goals Harvest Health Homeostasis Human Hyperglycemia Incidence Inflammation Inner mitochondrial membrane Instruction Insulin Resistance Intervention Investigation Lead Lymphocyte Measurement Measures Membrane Potentials Mentors Mentorship Messenger RNA Methodology Mitochondria Mitochondrial Proteins Mononuclear Nitric Oxide Non-Insulin-Dependent Diabetes Mellitus Nuclear Outcome Oxidation-Reduction Oxidative Phosphorylation Oxides Participant Pathology Patients Phenotype Play Population Process Production Reactive Oxygen Species Regulation Research Research Personnel Research Training Resolution Risk Role Signal Transduction Source Techniques Thrombosis Training Training Programs Ultrasonography Vascular Endothelium Vasodilation Vasodilator Agents Wisconsin arteriole cardiovascular risk factor career development computerized tools design diabetic experience human data human tissue improved insight macrovascular disease medical schools mitochondrial membrane monocyte non-diabetic novel marker paracrine programs skills subcutaneous vascular endothelial dysfunction vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): The applicant has designed this proposal to be an intensive educational and research experience that will allow him to earn key skills to become an independent translational investigator applying the tools of computational genomics and bioinformatics to the study vascular biology and the development of atherosclerosis. To this end, the Medical College of Wisconsin provides an ideal setting for this training. The applicant's mentor, Dr. David Gutterman, is an internationally recognized expert in the study of endothelial function. Through collaborations with Drs. UN Broeckel, Daniel Beard, and Craig Struble, he will receive exceptional training in genomic research and have wide exposure to experts in genetic research and the field of bioinformatics. The vascular endothelium plays a key role in maintaining vascular homeostasis. Endothelium-derived nitre oxide (NO) is a key paracrine actor responsible for maintaining endothelial homeostasis. Excessive reactive oxygen species (ROS) production in Type II diabetics leads to a decrease in bioavailable NO, making the endothelium "dysfunctional". This leads to phenotypic changes that promote the development of atherosclerosis. Recent data suggest hyperpolarization of the inner mitochondrial membrane is an important source of excessive ROS in type 2 diabetics. Excessive ROS leads to a loss of mitochondria mass, altered transcription of mitochondrial-associated genes, and finally a loss of bioavailable NO . The applicant has designed a set of investigations to assess novel markers of mitochondrial homeostasis (mitochondrial membrane potential, mitochondrial mass, mitochondrial ROS production, and oxidative phophorylation- related gene transcription) in type 2 diabetics and healthy humans. First, we will compare these measures of mitochondrial homeostasis to measures of endothelial function in diabetics and non-diabetics. Second, we will determine whether interfering with mitochondrial hyperpolarization that occurs in diabetes with by partial uncoupling of oxidative phosporylation improves endothelial function and reduces ROS production in these patients.

描述（由申请人提供）：申请人将此提案设计为密集的教育和研究经验，这将使他获得关键技能，成为一名独立的转化研究者，应用计算基因组学和生物信息学工具来研究血管生物学和动脉粥样硬化的发展。为此，威斯康星医学院为此次培训提供了理想的环境。申请人的导师David Gutterman博士是国际公认的内皮功能研究专家。通过与博士的合作。在 UN Broeckel、Daniel Beard 和 Craig Struble 的带领下，他将接受基因组研究方面的特殊培训，并广泛接触基因研究和生物信息学领域的专家。血管内皮在维持血管稳态中起着关键作用。内皮源性一氧化氮 (NO) 是负责维持内皮稳态的关键旁分泌因子。 II 型糖尿病患者产生过多的活性氧 (ROS) 会导致生物可利用的一氧化氮 (NO) 减少，从而使内皮细胞“功能失调”。这导致表型变化，促进动脉粥样硬化的发展。最近的数据表明，线粒体内膜的超极化是 2 型糖尿病患者体内过量 ROS 的重要来源。过多的 ROS 会导致线粒体质量的损失、线粒体相关基因转录的改变，最后导致生物可利用的 NO 的损失。申请人设计了一系列研究来评估2型糖尿病患者和健康人线粒体稳态的新标志物（线粒体膜电位、线粒体质量、线粒体ROS产生和氧化磷酸化相关基因转录）。首先，我们将比较糖尿病患者和非糖尿病患者的线粒体稳态测量与内皮功能测量。其次，我们将确定通过氧化磷酸化部分解偶联干扰糖尿病中发生的线粒体超极化是否可以改善这些患者的内皮功能并减少 ROS 产生。