Redox Regulation of DJ-1 Function

DJ-1 功能的氧化还原调节

基本信息

批准号：
8516532
负责人：
Mark A. Wilson
金额：
$ 25.79万
依托单位：
UNIVERSITY OF NEBRASKA LINCOLN
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8516532
关键词：
Affect Affinity Aging-Related Process Animal Model Animals Apoptosis Binding Biochemical Biochemistry Biological Models Cell Culture Techniques Cells Communities Complement Cysteine Cytoprotection Data Disease Drosophila genus Drosophila melanogaster Escherichia coli Etiology Eukaryota Generations Genetic Goals Homeostasis Homologous Gene Human Knock-out Knowledge Lead Maintenance Malignant Neoplasms Messenger RNA Mitochondria Modification Molecular Mutation Neurodegenerative Disorders Organism Oxidation-Reduction Oxidative Regulation Oxidative Stress PARK7 protein Parkinsonian Disorders Pathogenesis Play Post-Translational Protein Processing Prokaryotic Cells Protein Family Proteins Proteome Publications RNA Binding Regulation Research Roentgen Rays Role Scientist Stroke Structure Structure-Activity Relationship System Testing Therapeutic Transcript Translations Work X-Ray Crystallography base biological adaptation to stress cell type cysteine sulfinic acid design effective therapy expectation experience human disease improved in vivo innovation insight macromolecule member mitochondrial dysfunction oxidation protein function public health relevance sensor therapy development

项目摘要

DESCRIPTION (provided by applicant): Oxidative stress and mitochondrial dysfunction are centrally involved in the etiology of several diseases and in the normal process of aging. The protein DJ-1 is an oxidative stress response protein whose absence or dysregulation has been implicated in parkinsonism, cancer, and stroke. DJ-1 can robustly protect cells against multiple forms of oxidative stress and thereby confer protection against degeneration that can lead to disease. The molecular mechanism(s) of DJ-1's action, however, remains unclear. DJ-1 contains a functionally essential cysteine residue whose oxidation is hypothesized to regulate its cytoprotective function. We will investigate the mechanism by which DJ-1 senses and responds to oxidative stress by accomplishing three specific aims. The first aim will investigate the role of DJ-1 cysteine oxidation in the protection against oxidative stress in the Drosophila animal model system. We will combine X-ray crystallography, biochemistry, and Drosophila genetics to establish a powerful animal model for the redox regulation of DJ-1 function. The second aim will determine the structure-function relationships for an established mRNA binding activity of DJ-1. The results will be used to test the hypothesis that conserved structural features near the oxidized cysteine integrate the RNA binding and redox sensing functions of DJ-1. The third aim will use a prokaryotic model system to investigate the evolutionarily conserved mechanism of DJ-1 protective function. The results will be used to test existing hypotheses about the conservation of regulatory cysteine oxidation in DJ-1 function as well as discover new functions for DJ-1. In total, the proposed research will provide a comprehensive molecular basis for understanding the oxidative regulation and pathogenic disruption of DJ-1 function. Ultimately, the results of this research will be used to design a new generation of therapeutics that enhance the protective function of DJ-1 in vulnerable cell types. PUBLIC HEALTH RELEVANCE: Oxidative stress and mitochondrial dysfunction are centrally involved in several human diseases. Major recent advances have identified DJ-1 as a protein that confers robust protection against oxidative stress. The precise biochemical function of DJ-1, however, remains uncertain. The long-term goal of this proposal is to determine the biochemical functions of DJ-1 that confer protection against oxidative stress and with the goal of developing therapies that improve the protective function of DJ-1.

描述（由申请人提供）：氧化应激和线粒体功能障碍集中参与了几种疾病的病因和正常衰老过程。蛋白DJ-1是一种氧化应激反应蛋白，其缺乏或失调与帕金森氏症，癌症和中风有关。 DJ-1可以牢固地保护细胞免受多种形式的氧化应激，从而防止可能导致疾病的变性。然而，DJ-1作用的分子机制尚不清楚。 DJ-1包含一个在功能上必不可少的半胱氨酸残基，其氧化被假设以调节其细胞保护功能。我们将通过实现三个特定目标来研究DJ-1感知并响应氧化应激的机制。第一个目的将研究DJ-1半胱氨酸氧化在果蝇模型系统中氧化应激中的作用。我们将结合X射线晶体学，生物化学和果蝇遗传学，为DJ-1功能的氧化还原调节建立强大的动物模型。第二个目标将确定DJ-1已建立的mRNA结合活性的结构 - 功能关系。结果将用于检验以下假设：氧化半胱氨酸附近的保守结构特征会整合DJ-1的RNA结合和氧化还原传感功能。第三个目标将使用原核模型系统研究DJ-1保护功能的进化保守机制。结果将用于测试有关DJ-1功能中调节性半胱氨酸氧化的现有假设，并发现DJ-1的新功能。总的来说，拟议的研究将为理解DJ-1功能的氧化调节和致病性破坏提供全面的分子基础。最终，这项研究的结果将用于设计新一代的治疗剂，以增强DJ-1在脆弱细胞类型中的保护功能。公共卫生相关性：氧化应激和线粒体功能障碍在几种人类疾病中集中参与。最近的主要进步已将DJ-1确定为一种蛋白质，可赋予氧化应激的强大保护。但是，DJ-1的精确生化功能仍然不确定。该提案的长期目标是确定DJ-1的生化功能，从而赋予氧化应激的保护以及开发改善DJ-1保护功能的疗法。