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: 7232281
• 负责人: STEPHEN C BONDY
• 金额: $ 28.24万
• 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/7232281
• 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（由申请方提供）：衰老是一个多因素过程，似乎与氧化和炎症事件增加相关。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将被研究，重点是这两个过程。在对广泛的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北方印迹法评估用褪黑激素处理老年小鼠后基因表达的变化。将强调与炎症或促氧化事件相关的那些基因的调查。将寻求导致基因组调节的胞质途径。将使用ELISA和Western试验定量可能受mRNA水平改变影响的蛋白质水平。将评价褪黑激素恢复线粒体功能完整性和延缓年龄相关的线粒体DNA缺失的能力。从固定的组织切片的特定肽的免疫组织化学鉴定将允许观察到的任何变化的更精确的定位。将通过比较给药小鼠的mRNA和蛋白质模式与较年轻动物的mRNA和蛋白质模式，评价与年龄相关的趋势停滞或逆转。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。生物变化和行为变化之间的协调程度可能意味着因果关系。研究结果将有助于发展一个合理的策略，延缓脑老化的进展。这也可能与减缓年龄是主要辅助因素的几种神经退行性疾病的发作和降低其发病率有关。