Development of mitochondrially targeted antioxidants for diabetic therapy

开发用于糖尿病治疗的线粒体靶向抗氧化剂

基本信息

批准号：
7586059
负责人：
VICTOR M DARLEY-USMAR
金额：
$ 37.63万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7586059
关键词：
Alabama Animal Disease Models Animal Model Antioxidants Cardiac Cardiac Myocytes Cell Culture System Cell Culture Techniques Cell Death Cell model Cells Cellular biology Clinical Coupled Data Defect Development Diabetes Mellitus Drug Delivery Systems Elements England Enzymes Etiology Exposure to Functional disorder Glucose Heart Hyperglycemia Insulin Resistance Lipid Peroxidation Lipids Measurement Mediating Medical Research Mitochondria Mitochondrial DNA Mitochondrial Proteins Modeling Modification Muscle Mitochondria Myocardium Non-Insulin-Dependent Diabetes Mellitus Organelles Oxidative Stress Oxygen Patients Peroxonitrite Physiological Play Post-Translational Protein Processing Prevention Production Proteins Proteome Proteomics Rattus Reactive Nitrogen Species Research Personnel Role Screening procedure Series Skeletal Muscle Streptozocin Sulfhydryl Compounds Superoxides Testing Therapeutic Index Therapeutic Intervention Thioctic Acid Tocopherols Tyrosine Universities Wisconsin analog base chemical synthesis design diabetic diabetic rat in vivo indexing insight medical schools mitochondrial dysfunction mouse model nitration novel prevent respiratory protein response tempol therapeutic target

项目摘要

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.

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发挥着重要作用，并为治疗干预提供了潜在目标。高血糖会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 DMA 的翻译后修饰。该提案的目标是开发线粒体靶向药物，增加细胞内 ROS 或 RNS 的降解，以纠正与糖尿病细胞和动物模型中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，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方面的专业知识。该联盟有能力设计、表征和优化大量线粒体抗氧化剂，以评估该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、mtDNA 损伤和因高血糖而发生的心脏功能障碍。将使用线粒体蛋白质组学、细胞生物学和生理学方法来检验这一假设，通过追求以下具体目标来模拟糖尿病：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。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。通过实现这些具体目标而获得的见解将定义成功设计线粒体靶向疗法的必要要素。这将为优化此类化合物在糖尿病临床中的应用奠定基础。