Importance of Mitochondria in the Endothelial Dysfunction of Type 2 Diabetes

申请者描述(由申请人提供)：申请者将此计划设计为一种密集的教育和研究经验，使他能够获得关键技能，成为一名独立的翻译调查员，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，威斯康星州医学院为这一培训提供了理想的环境。申请者的导师David Gutterman博士是国际公认的内皮功能研究专家。通过与UN Broeckel博士、Daniel Beard博士和Craig Struble博士的合作，他将接受基因组研究方面的特殊培训，并与基因研究和生物信息学领域的专家广泛接触。血管内皮细胞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)是维持内皮细胞动态平衡的关键旁分泌因子。II型糖尿病患者体内过多的活性氧(ROS)产生会导致生物可利用NO的减少，从而使内皮功能“失调”。这会导致表型变化，从而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ROS过高的重要来源。过量的ROS导致线粒体质量丧失，线粒体相关基因转录改变，最终导致生物可利用NO的损失。申请人设计了一系列调查，以评估线粒体稳态的新标记物(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)在2型糖尿病患者和健康人中的作用。首先，我们将比较糖尿病患者和非糖尿病患者线粒体稳态的这些指标与内皮功能的指标。其次，我们将确定是否通过部分解偶联氧化磷酸化来干扰糖尿病患者的线粒体超极化，从而改善内皮功能并减少这些患者的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.