Importance of Mitochondria in the Endothelial Dysfunction of Type 2 Diabetes

描述（由申请人提供）：申请人已将此提案设计为强化教育和研究经验，使其能够获得关键技能，成为独立的翻译研究者，将计算基因组学和生物信息学的工具应用于研究血管生物学和动脉粥样硬化的发展。为此，威斯康星州医学院提供了一个理想的设置为这种培训。申请人的导师大卫Gutterman博士是国际公认的内皮功能研究专家。通过与UN Broeckel、丹尼尔比尔德和克雷格斯特鲁布尔博士的合作，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内环境稳定中起着关键作用。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型糖尿病患者中过量的活性氧（ROS）产生导致生物可利用的NO减少，使内皮“功能障碍”。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型糖尿病患者中过量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的NO的损失。申请人设计了一组研究以评估2型糖尿病患者和健康人中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，我们将比较这些线粒体稳态的措施，糖尿病患者和非糖尿病患者的内皮功能的措施。其次，我们将确定是否通过氧化磷酸化的部分解偶联来干扰糖尿病患者中发生的线粒体超极化，从而改善内皮功能并减少这些患者中的ROS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.