Development of mitochondrially targeted antioxidants for diabetic therapy

描述（由申请人提供）：由ROS/RNS产生变化介导的线粒体功能障碍在糖尿病病因学中起重要作用，并为治疗干预提供了潜在靶点。高血压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、心脏功能障碍和最终的细胞死亡来评估。导致这些变化的潜在机制主要来自线粒体蛋白和线粒体DNA的翻译后修饰。该提案的目的是开发增加细胞内ROS或RNS降解的脑靶向药物，用于校正糖尿病细胞和动物模型中与高血糖症相关的线粒体缺陷。它涉及来自威斯康星州医学院和伯明翰的亚拉巴马大学的研究人员组成的财团，并结合了ROS/RNS测量，新型神经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，表征和优化线粒体抗氧化剂，以大量评估疾病动物模型的功效。据推测，线粒体靶向抗氧化剂将改善线粒体蛋白的ROS/RNS依赖性修饰、线粒体DNA损伤和因高糖而发生的心功能障碍。将使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检验该假设以模拟糖尿病：1：合成和优化经设计以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的脑靶向抗氧化剂。具体目标2：在细胞培养系统中筛选神经靶向抗氧化剂。具体目标3：确定脑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获得的见解将定义成功设计脑靶向治疗的必要元素。然后，这将作为优化此类化合物用于糖尿病临床用途的前奏。

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.