Contribution of m-tyrosine to the adverse effects of oxidative stress

间酪氨酸对氧化应激不利影响的贡献

• 批准号: 9248784
• 负责人: Brett Ipson
• 金额: $ 3.33万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9248784
• 关键词: Adverse effects; Affect; Age; Aging; Alzheimer' s Disease; Amino Acids; Animal Model; Animals; Antioxidants; Apoptosis; Apoptotic; Atherosclerosis; Biochemical; Biological Markers; Caenorhabditis elegans; Cataract; Cell Death; Cells; Charge; Chemicals; Deamination; Development; Diabetes Mellitus; Disease; Enzymes; Event; Exposure to; Fertility; Gene Mutation; Genes; Genetic Screening; Hydrophobicity; Hydroxyl Radical; In Vitro; Induction of Apoptosis; Isomerism; Lead; Leadership; Light; Link; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Morphology; Nitrogen; Organism; Orthologous Gene; Oxidative Stress; Oxides; Oxygen; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patient Care; Phenotype; Phenylalanine; Physicians; Plants; Play; Positioning Attribute; Preparation; Process; Production; Protein Biosynthesis; Proteins; Pyruvate; Reporter; Research; Research Project Grants; Research Training; Resistance; Role; Scientist; Surrogate Markers; Testing; Toxic effect; Training; Tyrosine; Tyrosine Aminotransferase; Tyrosine Metabolism Pathway; age related; amino acid metabolism; base; biological adaptation to stress; career; career development; cell injury; cytotoxicity; design; experimental study; forward genetics; genetic manipulation; hydroxyl group; improved; in vivo; innovation; mutant; novel; novel therapeutics; phenylalanine-tRNA; prevent; protective effect; protein structure; public health relevance; response; symposium; transcription factor

 DESCRIPTION (provided by applicant): Oxidative stress increases with age and likely contributes to a variety of age-related diseases, but the processes by which oxidative stress causes cellular damage and contributes to aging and its associated pathologies are not completely understood. This proposal seeks to study the role of atypical tyrosine isomers, which differ from endogenous tyrosine in the positioning of their hydroxyl group on the benzyl ring, in the harmful effects of oxidative stress. Under conditions of oxidative stress, hydroxyl radicals can attack the benzyl ring of phenylalanine and form these abnormal tyrosine isomers including meta-tyrosine. For decades elevations in m-tyrosine concentrations have been measured simply as a surrogate marker of oxidative stress burden. However, emerging evidence suggests m-tyrosine is directly harmful to cells and may actually contribute to oxidative stress-induced cell damage and disease pathogenesis. A proposed mechanism for the harmful effects of m-tyrosine is the aberrant charging of this amino acid to phenylalanine-tRNA which then results in the subsequent incorporation of m-tyrosine into newly synthesized proteins. Potentially this could have a range of effects on these proteins given the chemical differences between the hydrophobic phenylalanine and the polar m-tyrosine residue, but the ultimate downstream consequences triggered by these substitutions remain unexplored. The proposed project seeks to utilize the model organism C. elegans to elucidate the downstream pathways by which m-tyrosine is toxic to cells, perhaps via the induction of apoptotic pathways, and to also explore a novel role for the enzyme tyrosine aminotransferase within the cellular antioxidant response by metabolizing m-tyrosine and hence preventing incorporation into proteins. Three aims have been designed to assess this hypothesis. Because the C. elegans germline is significantly altered following exposure to m-tyrosine, Aim 1 will determine whether m-tyrosine adversely affects the C. elegans germline by inducing apoptosis. Aim 2 will determine whether tyrosine aminotransferase can catalyze the metabolism of m-tyrosine and thus reduce its toxic effects both in vitro and in vivo. Aim 3 will use novel resistance mutants that were recently identified in a forward genetic screen to study cellular pathways essential for m-tyrosine toxicity. The successful completion of this project will extend the current understanding of how m-tyrosine generated by oxidative stress contributes to cell toxicity and disease pathology. Furthermore, these studies would define a novel role for tyrosine aminotransferase within the cellular antioxidant response through the elimination of toxic tyrosine isomers. The results from this project may in turn lead to the development of new therapies for age-associated diseases in which m-tyrosine plays a direct pathologic role. In addition to the research project, the proposal also includes a training component involving coursework, conferences, and career development activities to promote the trainee's development into a physician-scientist who will be able to have a leadership role in research and patient care.

 描述（由申请人提供）：氧化应激随着年龄的增长而增加，并可能导致各种与年龄相关的疾病，但氧化应激导致细胞损伤并导致衰老及其相关病理的过程尚未完全了解。该提案旨在研究非典型酪氨酸异构体的作用，其不同于内源性酪氨酸的羟基在苄基环上的定位，在氧化应激的有害影响。在氧化应激条件下，羟基自由基可以攻击苯丙氨酸的苄基环并形成这些异常的酪氨酸异构体，包括间酪氨酸。几十年来，m-酪氨酸浓度的升高一直被简单地作为氧化应激负荷的替代标志物进行测量。然而，新出现的证据表明，间酪氨酸是直接有害的细胞，实际上可能有助于氧化应激诱导的细胞损伤和疾病的发病机制。间-酪氨酸的有害作用的一种提出的机制是这种氨基酸对苯丙氨酸-tRNA的异常充电，然后导致间-酪氨酸随后掺入新合成的蛋白质中。考虑到疏水性苯丙氨酸和极性间酪氨酸残基之间的化学差异，这可能对这些蛋白质产生一系列影响，但这些取代引发的最终下游后果尚未探索。拟议的项目旨在利用模式生物C。elegans来阐明m-tyrosine对细胞有毒的下游途径，可能是通过诱导凋亡途径，并且还探索酪氨酸氨基转移酶在细胞抗氧化反应中通过代谢m-tyrosine从而防止掺入蛋白质的新作用。我们设计了三个目标来评估这一假设。因为C.间-酪氨酸对线虫生殖细胞系的影响，目的1将确定间-酪氨酸是否对线虫生殖细胞系产生不利影响。elegans胚系诱导细胞凋亡。目的二是研究酪氨酸氨基转移酶是否能催化间酪氨酸的代谢，从而降低其体内外毒性作用。Aim 3将使用最近发现的新的抗性突变体， 正向遗传筛选，以研究对m-酪氨酸毒性至关重要的细胞途径。该项目的成功完成将扩展目前对氧化应激产生的m-酪氨酸如何促进细胞毒性和疾病病理学的理解。此外，这些研究将通过消除有毒酪氨酸异构体来确定酪氨酸氨基转移酶在细胞抗氧化反应中的新作用。该项目的结果可能反过来导致年龄相关疾病的新疗法的开发，其中m-酪氨酸起着直接的病理作用。除了研究项目，该提案还包括涉及课程，会议和职业发展活动的培训部分，以促进受训者发展成为能够在研究和患者护理中发挥领导作用的医生科学家。