Development of mitochondrially targeted antioxidants for diabetic therapy

描述(申请人提供)：线粒体功能障碍，由ROS/RNS产生的变化介导，在糖尿病的病因中起着重要作用，并为治疗干预提供了一个潜在的靶点。高血糖导致进行性线粒体损伤，这可以通过线粒体蛋白质组的变化、心脏功能障碍以及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质和线粒体DNA的翻译后修饰。这项建议的目标是开发线粒体靶向药物，增加细胞内ROS或RNS的降解，以纠正细胞和动物糖尿病模型中与高血糖相关的线粒体缺陷。它涉及来自威斯康星医学院和伯明翰阿拉巴马大学的研究人员联盟，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的专业知识。该联盟有能力设计、表征和优化大量的线粒体抗氧化剂，以评估这种疾病的动物模型的疗效。据推测，线粒体靶向抗氧化剂将改善高糖引起的线粒体蛋白ROS/RNS依赖的修饰、线粒体DNA损伤和心功能障碍。这一假说将利用线粒体蛋白质组学、细胞生物学和生理学方法通过追求以下具体目标来建立糖尿病模型：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歧化、脂质自由基和过氧亚硝酸盐的稳态水平。具体目标2：在细胞培养系统中筛选线粒体靶向抗氧化剂。具体目标3：确定线粒体靶向抗氧化剂对糖尿病动物模型中诱导的线粒体功能障碍的影响。通过实现这些特定目标而获得的洞察力将确定成功设计线粒体靶向疗法的必要要素。这将作为优化此类化合物用于糖尿病临床使用的前奏。

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.