Development of mitochondrially targeted antioxidants for diabetic therapy

描述（由申请人提供）：线粒体功能障碍，由ROS/RNS产生的变化介导，在糖尿病的病因学中起着重要作用，并为治疗干预提供了潜在的靶点。高血糖导致进行性线粒体损伤，可通过线粒体蛋白质组改变、心功能障碍和最终细胞死亡来评估。导致这些变化的潜在机制主要来自线粒体蛋白和线粒体DMA的翻译后修饰。该建议的目的是开发线粒体靶向药物，增加细胞内ROS或RNS的降解，以纠正糖尿病细胞和动物模型中与高血糖相关的线粒体缺陷。该项目由威斯康星医学院和阿拉巴马大学伯明翰分校的研究人员组成，并结合了ROS/RNS测量、新型线粒体靶向抗氧化剂的化学合成、线粒体蛋白质组学以及糖尿病细胞和动物模型等方面的专业知识。该联盟有能力设计、表征和优化线粒体抗氧化剂，以评估该疾病动物模型的疗效。据推测，线粒体靶向抗氧化剂将改善ROS/RNS依赖性线粒体蛋白修饰、mtDNA损伤和高血糖时发生的心功能障碍。这一假设将通过线粒体蛋白质组学、细胞生物学和生理学方法来验证，通过追求以下具体目标：1：合成和优化线粒体靶向抗氧化剂，旨在降低线粒体内超氧化物、脂质自由基和过氧亚硝酸盐的稳态水平。特异性目标2：细胞培养系统中线粒体靶向抗氧化剂的筛选。特定目的3：确定线粒体靶向抗氧化剂对糖尿病动物模型诱导的线粒体功能障碍的影响。通过完成这些特定目标而获得的见解将定义成功设计线粒体靶向治疗的必要元素。这将作为优化这些化合物用于糖尿病临床应用的前奏。

DESCRIPTION (provided by applicant): Mitochondrial dysfunction, mediated by changes in the production of ROS/RNS, plays an important role in the etiology of diabetes and offers a potential target for therapeutic intervention. Hyperglycemia results in progressive mitochondrial damage which can be assessed by changes in the mitochondrial proteome, cardiac dysfunction, and ultimately cell death. The underlying mechanisms leading to these changes have a major contribution from the post-translational modification of mitochondrial proteins and mitochondrial DMA. This proposal has the objective of developing mitochondrially targeted drugs that increase the degradation of intracellular ROS or RNS for the correction of the mitochondrial defects associated with hyperglycemia in cell and animal models of diabetes. It involves a consortium of investigators from the Medical College of Wisconsin and the University of Alabama at Birmingham and combines expertise in the measurement of ROS/RNS, the chemical synthesis of novel mitochondrially targeted antioxidants, mitochondrial proteomics and cell and animal models of diabetes. The consortium has the ability to design, characterize and optimize mitochondrial antioxidants in the large quantities necessary for assessment of efficacy in animal models of the disease. It is hypothesized that mitochondrially targeted antioxidants will ameliorate the ROS/RNS dependent modification of mitochondrial proteins, mtDNA damage and cardiac dysfunction that occurs in response to high glucose. This hypothesis will be examined using mitochondrial proteomics, cell biology and physiological approaches to model diabetes through pursuit of the following Specific Aims: 1: Synthesis and optimization of mitochondrially targeted antioxidants designed to decrease steady state levels of intra- mitochondrial superoxide, lipid radicals and peroxynitrite. Specific Aim 2: Screening of mitochondrially targeted antioxidants in cell culture systems. Specific Aim 3: Determine the impact of mitochondrially targeted antioxidants on mitochondrial dysfunction induced in an animal model of diabetes. The insights gained by the accomplishment of these specific aims will define the necessary elements for the successful design of mitochondrially targeted therapeutics. This would then act as the prelude to optimization of such compounds for clinical use in diabetes.