MECHANISMS LEADING TO ENHANCED TOLERANCE TO OXIDATIVE STRESS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 拟南芥抗氧化能力增强和寿命延长的机制 需氧生物体的代谢由于活性氧（ROS）的形成而导致氧化损伤的各种风险。虽然有相当多的证据表明氧化应激与衰老有关，但我们对这一过程中所涉及的潜在生化机制的认识存在明显的差距。维生素C（抗坏血酸，阿萨），一种强大的非酶活性氧清除剂，是抗氧化细胞能力的主要贡献者。跨界发现阿萨以非常高的浓度存在于多个亚细胞区室中，包括线粒体、细胞质、内质网（ER）和叶绿体。本研究组的主要目标是了解阿萨代谢及其在赋予植物对氧化应激的耐受性从而延缓衰老中的作用。特别是，我们专注于肌醇途径的阿萨的研究。我们的初步数据表明，葡萄糖醛酸内酯酶（GNL）和古洛糖酸-1，4-内酯氧化酶（GLOase）的一些亚型的线粒体，ER，和叶绿体的目标。本项目的长期目标是利用我们开发的独特而强大的工具来研究亚细胞阿萨库在导致对氧化应激和延迟衰老的耐受性的潜在生化机制中的作用。我们假设植物已经进化出GNL和GLOase的同种型，其维持阿萨亚细胞库，所述亚细胞库需要保护必需的和脆弱的分子免受氧化应激，并且这种保护对于我们已经开发的高阿萨拟南芥品系所显示的增加的寿命、增强的生长和延长的生殖活性至关重要。具体目标13将测试这个假设。目标1：研究推定的线粒体GLOase At 5g 56470在促进线粒体阿萨亚细胞库、保护免受氧化应激和延长寿命中的作用。目标二：探索ER靶向GNL和GLOases在维持氧化还原平衡中的作用，这有助于正确的ER功能，保护免受氧化应激和延长寿命。目标3：评估推定的叶绿体GNL At 1g 56500在促进叶绿体阿萨亚细胞库、保护免受氧化应激和延长寿命方面的作用。公共卫生相关性：这项研究的结果将直接影响我们对阿萨延缓衰老机制的理解，并对人类和动物健康产生明确的影响。该项目还将促进已经参与这项研究的年轻科学家的不断增长，为INBRE的使命做出明确的贡献。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Mechanisms Leading to Enhanced Tolerance to Oxidative Stress and Increased Lifespan in Arabidopsis The metabolism of aerobic organisms leads to various risks for oxidative damage, due to the formation of reactive oxygen species (ROS). Although there is considerable evidence implicating oxidative stress in aging, there is a clear gap in our knowledge of the underlying biochemical mechanisms involved in this process. Vitamin C (ascorbate, AsA), a powerful non-enzymatic ROS scavenger, is a major contributor to the antioxidant cell capacity. Across kingdoms AsA is found at very high concentrations in multiple subcellular compartments including the mitochondria, cytoplasm, endoplasmic reticulum (ER), and chloroplast. A major objective of my group is to understand AsA metabolism and its role in conferring plants tolerance to oxidative stress and thus in delaying aging. In particular we focus on the study of the inositol pathway to AsA. Our preliminary data indicate that some of the isoforms of glucuronolactonase (GNL) and gulono-1,4-lactone oxidase (GLOase) are targeted to the mitochondria, ER, and chloroplast. The long-term goal of this project is to take advantage of the unique and powerful tools we have developed to investigate the role of subcellular AsA pools in the underlying biochemical mechanisms leading to tolerance to oxidative stress and delayed aging. We hypothesize that plants have evolved isoforms of GNL and GLOase that maintain AsA subcellular pools needed to protect essential and vulnerable molecules against oxidative stress, and that this protection is critical for the increased lifespan, enhanced growth, and extended reproductive activity displayed by the high-AsA Arabidopsis lines we have developed. Specific Aims 13 will test this hypothesis. Aim 1: Investigate the role of the putative mitochondrial GLOase At5g56470 in contributing to the mitochondrial AsA subcellular pool, to protection against oxidative stress, and to increased lifespan. Aim 2: Explore the role of ER-targeted GNLs and GLOases in maintaining a redox balance conducive to proper ER function, protection against oxidative stress, and increased lifespan. Aim 3: Evaluate the role of the putative chloroplastic GNL At1g56500 in contributing to the chloroplast AsA subcellular pool, to protection against oxidative stress, and to increased lifespan. Public Health Relevance: The results of the proposed research will have direct impact on our understanding of the mechanisms by which AsA delays aging, with clear implications for human and animal health. This project will also contribute to the growing pipeline of young scientists already involved in this research, making a clear contribution to the INBRE mission.