Caveolae as capacitors for oxygen

小凹作为氧气电容器

• 批准号: 9245289
• 负责人: Hemal H Patel
• 金额: $ 20.97万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9245289
• 关键词: Age; Aging; Biochemical; Biochemical Process; Biological; Biological Process; Biology; Caenorhabditis elegans; Cardiovascular system; Caveolae; Caveolins; Cell physiology; Cells; Cessation of life; Cholesterol; Clams; Cyanobacterium; Dinosaurs; Elderly; Energy-Generating Resources; Eukaryotic Cell; Event; Evolution; Extinction (Psychology); Failure; Free Radicals; Gene Expression Regulation; Generations; Genetic; Goals; Growth; Human; Illusions; Knowledge; Life; Link; Longevity; Malignant Neoplasms; Membrane; Membrane Microdomains; Mental disorders; Metabolic; Metabolism; Mitochondria; Mitotic; Molecular; Mus; Mutation; Natural Resources; Neurodegenerative Disorders; Organ; Organism; Oxidation-Reduction; Oxidative Phosphorylation; Oxygen; Photosynthesis; Physiological; Planet Earth; Planets; Post-Translational Protein Processing; Protons; Reaction; Regulation; Role; Rosa; Scaffolding Protein; System; Tissues; Toxic effect; Water; Youth; age related; environmental stressor; healthy aging; man; oxygen toxicity; planetary Atmosphere; response; theories; virtual

ABSTRACT The life span of organisms differs widely among species: C. elegans live 14-25 days, mice for a couple of years, humans into their eighties on average, and organisms such as the giant clam can live upwards of 500 years. There are likely conserved mechanisms that regulate the efficiency of cell function in youth that declines with age, ultimately resulting in systemic and organismal failure and death. In spite of the large number of ideas that have been proposed to account for the loss in efficiency and function as an organism ages, no common integrative theory for aging that is evolutionarily conserved has been advanced and thus, represents a major gap in knowledge. The oxygen paradox highlights the mystery that O2 is so critical a fuel for the metabolic machinery of life, yet so toxic to all forms of life inhabiting this planet. The key to this paradox are the two simple, yet biologically fundamental redox reactions: the first reaction, which is essentially the reverse of photosynthetic water splitting, marks the dawn of eucarya in which mitochondria `respire' oxygen to enzymatically generate proton gradient fueling oxidative phosphorylation and the second reaction where O2 in excess is consumed to generate reactive species that induce damage. To maximize the first reaction and minimize the second, life needed to maintain oxygen levels under tight control. It has been proposed that the evolutionary response to this paradox was to create cholesterol within membranes as a way to “tame” oxygen and allow for its biologic use as an energy source and as a primary feature that links membranes and metabolism. We hypothesize that caveolin, a scaffolding protein that organizes cholesterol into membrane microdomains, exists as a “capacitor” to create the efficiency of metabolism in youth through regulation of membrane oxygen and that with aging, caveolin expression is decreased in certain organs, thereby leading to increased oxygen toxicity. We further propose that this toxicity can be limited by re-expression of caveolin in the setting of advanced age. The following specific aims will be studies: Specific Aim 1: Determine what aspects of caveolin serve as membrane oxygen capacitors. Specific Aim 2: Determine the impact of age and caveolin expression on organ oxygen storage capacity and toxicity.

抽象的 生物的寿命在物种之间有很大不同：秀丽隐杆线虫活14-25天，几只小鼠 多年来，人类平均到八十年代，巨大蛤等生物可以生活在500多以上 年。可能有保守的机制调节年轻人细胞功能的效率下降 随着年龄的增长，最终导致系统性和有机衰竭和死亡。尽管有大量 提议说明效率损失和作为生物年龄的功能的想法，否 衰老的常见综合理论是进化配置的，因此已经提出了 知识的主要差距。氧悖论强调了一个神秘的O2是如此关键的燃料至关重要 生命的代谢机制，但对居住在这个星球的各种形式的生命都如此毒性。这个悖论的关键是 两种简单但具有生物学基本的氧化还原反应：第一反应，这实际上是相反的 光合作用水分裂，标志着线粒体氧的欧洲 酶促产生质子梯度加油氧化磷酸化和第二个反应，其中O2在 过量被消耗以产生诱导损伤的反应性物种。为了最大化第一个反应和 最小化第二个，使氧气水平保持在严格控制下所需的寿命。有人提出 对这种悖论的进化反应是在膜内产生胆固醇，以“驯服”氧气 并允许其生物学用作能源，并作为将膜和连接的主要特征 代谢。我们假设Caveolin是一种将胆固醇组织成膜的脚手架蛋白 微域是作为“电容器”而存在的 膜氧，随着衰老的衰老，小窝蛋白的表达在某些器官中降低，从而导致 氧毒性增加。我们进一步建议，这种毒性可以通过对小窝林的重新表达的限制 高龄的设置。以下具体目的将是研究：具体目标1：确定什么 小窝蛋白的各个方面用作膜氧气电容器。特定目标2：确定年龄的影响 可爱素在有机氧气储存能力和毒性上的表达。