ROS induced cellular toxicity and tissue damage

ROS诱导的细胞毒性和组织损伤

• 批准号: 7012539
• 负责人: ATANU DUTTAROY
• 金额: $ 20.38万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7012539
• 关键词: DNA damage; Drosophilidae; age difference; aging; apoptosis; clinical research; enzyme activity; enzyme linked immunosorbent assay; free radical oxygen; longevity; mitochondria; oxidative stress; oxidized lipid; superoxide dismutase; terminal nick end labeling

DESCRIPTION (provided by applicant): Reactive oxygen species (ROS) is seemingly the major determinant of life-span. To understand the aging potential of specific cell types or tissue we need to understand the effect of intracellular ROS toxicity on specific tissue in vivo. The creation of an intrinsic oxidative stress environment in specific tissue without affecting others was not easy until the advent of molecular-genetic tools. It is now possible to ask this question in vivo in model systems like Drosophila. The enzyme manganese superoxide dismutase, which catalyzes the detoxification of superoxide radicals in the mitochondrial matrix, plays a central role in cellular aging, as evident from the fact that loss of MnSOD function severely reduces organismic life span, while its over-expression could extend it. Hypothesis: The specific hypothesis to be tested is that depletion of MnSOD activity from a specific tissue will trigger cellular damage through an intracellular rise in ROS concentration; however, the amount of damage to individual tissues will vary, as will their biological efficacies, which will be reflected at the organismal level. We will examine our hypothesis in four different tissues in Drosophila including fat body, muscle, brain and retinal cells of the eye, all of which are essential for the viability of the organism with the exception of retinal cells. By using a state-of-the-art technique, MnSOD function will be depleted in vivo from each of these tissues. We will address several important biological questions involving tissue specific ROS generation, tissue specific oxidative damage to DNA and protein, tissue specific apoptotic cell death potential. Depletion of MnSOD function from each of these tissues will provide important insight regarding the contribution of ROS towards cellular aging.

描述（由申请人提供）：反应性氧（ROS）似乎是生命中的主要决定因素。要了解特定细胞类型或组织的衰老潜力，我们需要了解细胞内ROS毒性对体内特定组织的影响。在分子遗传学工具的出现之前，在没有影响他人的情况下创造了特定组织中固有的氧化应激环境并不容易。现在可以在果蝇等模型系统中在体内提出这个问题。锰超氧化物歧化酶催化了线粒体基质中超氧化物自由基的排毒，在细胞衰老中起着核心作用，这从MNSOD功能的丧失严重降低了有机体的寿命，而过度表达的可能会延长它。假设：要检验的特定假设是，从特定组织中耗尽MNSOD活性将通过ROS浓度的细胞内升高触发细胞损伤。但是，对单个组织的损害量将有所不同，它们的生物学功效也会有所不同，这将在生物水平上反映。我们将检查果蝇四种不同组织中的假设，包括脂肪体，肌肉，大脑和视网膜细胞，所有这些都对生物体的生存能力至关重要，除视网膜细胞外。通过使用最先进的技术，MNSOD功能将在每个组织中的体内耗尽。我们将解决涉及组织特异性ROS的几个重要生物学问题，组织特异性氧化损伤对DNA和蛋白质，组织特异性凋亡细胞死亡潜力。从这些组织中，MNSOD功能的耗竭将提供有关ROS对细胞衰老的贡献的重要见解。