Neurodegenration and Mitochnodrial Dysfunction in Aging

衰老过程中的神经退行性变和线粒体功能障碍

• 批准号: 7102616
• 负责人: STEPHEN C BONDY
• 金额: $ 29.08万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7102616
• 关键词: Neurodegenration; Mitochnodrial; Dysfunction; Aging

DESCRIPTION (provided by applicant): Senescence is a multifactorial process, which appears to be associated with increases in both oxidative and inflammatory events. The ability to slow or reverse changes associated with brain aging by dietary supplementation will be investigated with a focus on these two processes. Following an initial survey of a broad range of agents, melatonin has been selected for detailed study. Changes in gene expression following treatment of aged mice with melatonin will be evaluated using array technology in combination with Northern blotting. Investigation of those genes associated with inflammatory or pro-oxidant events will be emphasized. The cytosolic pathways leading to genomic modulation will be sought. Levels of proteins potentially affected by altered mRNA levels will be quantitated using ELISA and Western assays. The ability of melatonin to restore integrity of mitochondrial functioning and retard age-related mitochondrial DNA deletion will be evaluated. Immunohistochemical identification of specific peptides from fixed tissue sections will allow a more precise localization of any changes observed. Arrest or reversal of trends associated with age will be evaluated by comparison of patterns of mRNA and proteins from dosed mice with those from younger animals. Parallel studies using behavioral endpoints will reveal whether molecular changes detected, are reflected by altered cognition or motor strength. The degree of consonance between biological and behavioral changes may imply a causal relation. Results will contribute to development of a rational strategy for delaying progression of brain aging. This is also likely to be relevant to slowing the onset of, and reducing the incidence of, several neurodegenerative diseases where age is a major co-factor.

描述（由申请人提供）：衰老是一个多因素过程，似乎与氧化和炎症事件的增加有关。将研究通过膳食补充剂减缓或逆转与大脑衰老相关的变化的能力，重点关注这两个过程。在对多种药物进行初步调查后，选择褪黑激素进行详细研究。将使用阵列技术结合 Northern blotting 来评估用褪黑激素治疗老年小鼠后基因表达的变化。将强调对那些与炎症或促氧化事件相关的基因的研究。将寻找导致基因组调节的胞质途径。可能受 mRNA 水平改变影响的蛋白质水平将使用 ELISA 和 Western 检测进行定量。将评估褪黑激素恢复线粒体功能完整性和延缓与年龄相关的线粒体 DNA 缺失的能力。对固定组织切片中的特定肽进行免疫组织化学鉴定将能够更精确地定位观察到的任何变化。通过比较给药小鼠与年轻动物的 mRNA 和蛋白质模式，可以评估与年龄相关的趋势的停滞或逆转。使用行为终点的平行研究将揭示检测到的分子变化是否反映在认知或运动强度的改变上。生物学和行为变化之间的一致性程度可能意味着因果关系。结果将有助于制定延缓大脑衰老进程的合理策略。这也可能与减缓几种神经退行性疾病的发病率和降低发病率有关，其中年龄是主要的辅助因素。