Superoxide Dismutases and Ionic Manganese in Aging

描述(申请人提供)：这项研究的长期目标是在分子水平上了解氧化应激、金属代谢和衰老之间的联系。这项拟议的研究利用一种多细胞高等生物体--线虫(蠕虫)作为模型系统，研究抗氧化酶--超氧化物歧化酶(SOD)在氧化应激和衰老中的重要性。“氧化应激”是一个术语，用来描述一种细胞状态，即与抗氧化剂相比，自由基过多，并与许多人类疾病和衰老有关。超氧化物歧化酶是一类提供抗氧化防御超氧阴离子自由基的酶。也正是这种酶(以铜、锌的形式)在人类中发生突变时，会导致通常被称为卢·格里克病的衰弱神经退行性疾病。几乎所有的需氧生物，包括人类，都有肥胖症。线虫与大多数生物不同，在活性部位有5个超氧化物歧化酶，其中3个含有铜和锌，另外2个含有锰。这项研究的第一个目的是使用各种SOD缺失的蠕虫来检查与野生型蠕虫相比的任何表型差异。在模式生物中缺乏某些形式的超氧化物歧化酶与寿命缩短有关。这一特定目标的最终目的是了解各种形式的超氧化物歧化酶在线虫中的功能。氧化应激是导致衰老的因素之一，由于金属和氧化应激与各种神经退行性疾病有关，我们建议研究某些金属水平的变化如何对氧化应激和寿命产生影响。我们的主要关注点是锰，因为在单细胞生物中有越来越多的证据表明，体内的锰可以与磷酸盐或乳酸等配体形成络合物，并提供对氧自由基的防御。离子锰的真正作用尚不清楚，因为它也被证明是有毒的，会导致帕金森样综合症。第二个专门的目标是弄清楚锰离子是否具有类似于超氧化物歧化酶等酶的抗氧化特性。将改变蠕虫饲料中锰的有效性，并监测蠕虫体内的自由基水平、氧化损伤、内部金属水平和寿命，以进一步了解锰离子在体内所起的作用。

DESCRIPTION (provided by applicant): The long-term goal of this research is to understand at the molecular level, the link between oxidative stress, metal metabolism and aging. The proposed research utilizes a multi-cellular higher organism, the nematode C. elegans (worms), as a model system to investigate the importance of the antioxidant enzyme, superoxide dismutase (SOD), in oxidative stress and aging. "Oxidative stress" is a term that is used to describe a cellular condition when there is an excess of free radicals in comparison to antioxidants and has been linked to many human diseases as well as aging. Superoxide dismutases are the class of enzymes that provide antioxidant defense against superoxide radicals. Also it is this enzyme (in the copper, zinc form) that when mutated in humans causes the debilitating neurodegenerative disorder commonly known as Lou Gehrig's disease. Almost all aerobic organisms including humans have SODs. C. elegans unlike most organisms have 5 SODs, 3 containing copper and zinc and 2 others containing manganese, at the active site. The first aim of this study is to use various SOD deleted worms to examine for any phenotypic differences in comparison to the wild-type worms. The lack of some forms of SOD in model organisms have been linked with reduced life-span. The ultimate goal of this specific aim is to understand the functions of various forms of SODs in C. elegans. Oxidative stress is one of the factors responsible for aging and since metals and oxidative stress are implicated in various neurodegenerative disorders we propose to study how altered levels of certain metals can have an impact on oxidative stress and life-span. Our main focus is on manganese, as there is accumulating evidence in unicellular organisms suggesting that manganese in vivo can complex to ligands such as phosphate or lactate and provide defense against oxygen radicals. The true role of ionic manganese is not clearly understood yet as it is also documented to be toxic causing Parkinsonian-like syndrome. The second specific aim is devoted to figuring out if manganese ions have any antioxidant properties similar to enzymes such as SOD. Manganese availability in the diet of the worms will be altered and free radical levels, oxidative damage, internal metal levels, and life-span in the worms will be monitored to further our understanding of the roles played by manganese ions in vivo.