Importance of Mitochondria in the Endothelial Dysfunction of Type 2 Diabetes

描述（由申请人提供）：申请人将本计划书设计为密集的教育和研究经历，使他能够获得关键技能，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，威斯康星医学院为这一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。UN Broeckel， Daniel Beard和Craig Struble，他将接受基因组研究方面的特殊培训，并广泛接触遗传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）是维持内皮稳态的关键旁分泌因子。II型糖尿病患者过多的活性氧（ROS）产生导致生物可利用NO减少，使内皮“功能失调”。这导致表型改变，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型糖尿病患者过量ROS的重要来源。过量的ROS导致线粒体质量的损失，线粒体相关基因的转录改变，最终导致生物可利用NO的损失。申请人设计了一套研究来评估2型糖尿病患者和健康人线粒体稳态的新标记（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，我们将这些线粒体稳态测量与糖尿病患者和非糖尿病患者的内皮功能测量进行比较。其次，我们将确定在糖尿病患者中，通过氧化磷酸化的部分解偶联来干扰线粒体超极化是否能改善内皮功能并减少ROS的产生。

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.