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Effect of Antioxidants & Behavioral Enrichment on Gene Expression in Aged Canines

抗氧化剂的作用

基本信息

批准号：
7682850
负责人：
Elizabeth Head
金额：
$ 12.62万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7682850
关键词：
Age Aging Aging-Related Process Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloid deposition Animal Model Animals Antioxidants Apoptosis Archives Area Base of the Brain Behavioral Bioinformatics Biological Models Brain Canis familiaris Carnitine Categories Clinic Clinical Trials Cognition Cognitive Combined Modality Therapy Computer software Data Data Analyses Deposition Detection Diet Dietary Intervention Dietary Supplementation Dose Down-Regulation Employee Strikes Exercise Experimental Designs Freezing Funding Future Gene Expression Genes Genome Growth Factor Hippocampus (Brain)Human Human Genome Impaired cognition Individual Inflammation Intervention Intervention Studies Laboratories Lead Learning Link Lipids Maintenance Maps Measures Memory Metabolism Mitochondria Modeling Molecular Molecular Target Nature Nerve Degeneration Neurobiology Neuronal Dysfunction Neuronal Plasticity Neurons Outcome Measure Overlapping Genes Pathology Pathway interactions Pattern Process Protein Precursors Proteins Proteomics RNA Reagent Research Reverse Transcriptase Polymerase Chain Reaction Senile Plaques Signal Transduction Synaptic plasticity Technology Testing Thioctic Acid Time Tissue Sample Tissues Translating Treatment outcome Up-Regulation Vitamin E abeta accumulation age related aged aging brain base beta amyloid pathology brain tissue cognitive function cognitive training combinatorial environmental enrichment for laboratory animals experience feeding fruits and vegetables functional improvement functional outcomes improved innovation juvenile animal neurobiological mechanism neurogenesis neuron loss neuropathology normal aging novel therapeutics oxidative damage public health relevance research study response social treatment effect

项目摘要

DESCRIPTION (provided by applicant): During aging, there are a number of brain changes that may contribute to neuronal dysfunction and impaired cognition. Higher animal models are essential for understanding the molecular and cellular basis of brain aging. We have been using the aged canine (dog) model to identify key interventions and molecular mechanisms of brain aging. Age-dependent decline in memory and learning along with the progressive accumulation of oxidative damage, neuron loss and 2-amyloid (A2) deposition occur in the aging dog brain similar to that in the human. Canine A2 is identical to human A2, accumulates endogenously at levels similar to human and A2 plaque loads are correlated with cognitive function. Thus, this model system is useful for exploring links between aging, oxidative damage, A2 and cognition. We have used a dietary and an environmental enrichment intervention to determine if these can improve cognitive function singly and in combination. We have demonstrated that an antioxidant and mitochondrial co-factor dietary intervention improves learning and maintains cognitive function over a 2.8 year period of time in aged dogs. Along with improved learning we observe decreased A2 in antioxidant treated dogs and decreased oxidative damage using proteomics approaches. We have further shown that behavioral enrichment can also improve cognition but this occurs via a non- A2/plaque mechanism as A2 seems unaffected. Importantly, beneficial cognitive effects of the antioxidant diet or behavioral enrichment treatments alone were further enhanced when combined. At present, the molecular targets of each treatment and convergence points between the two treatments that lead to additive neuronal function improvements have yet to be established. The primary objective of this application is to take advantage of newly available technologies (Affymetrix Canine Genome Arrays) and utilize brain tissues from these same animals to further establish and map the neurobiological mechanisms underlying the cognitive improving effects of each treatment and the combined treatment. To accomplish these objectives the following aims are proposed: (1) To profile gene expression changes in the temporoparietal cortex as a function of age in dogs and; (2) To profile gene expression changes in aged dogs provided with either or both an antioxidant-enriched diet and behavioral enrichment. Further understanding of the pathways engaged by these two interventions may lead to new research hypotheses, treatments and outcome measures that may be directly translated to human clinical trials. PUBLIC HEALTH RELEVANCE: Profiling gene expression changes as a consequence of antioxidant diet and behavioral enrichment interventions in aged canines will allow us to identify and optimize new therapeutics for improving cognition in both normal aging individuals and those with Alzheimer's disease.

描述(申请人提供)：在衰老过程中，有一些大脑变化可能会导致神经元功能障碍和认知障碍。高等动物模型对于了解脑老化的分子和细胞基础是必不可少的。我们一直在使用老龄犬(狗)模型来确定大脑衰老的关键干预措施和分子机制。在老化的狗脑中，与人类相似，随着氧化损伤、神经元丢失和2-淀粉样蛋白(A2)沉积的逐渐积累，记忆和学习能力随着年龄的增长而下降。犬A2与人类A2相同，内源性蓄积水平与人类相似，A2斑块负荷与认知功能相关。因此，这个模型系统对于探索衰老、氧化损伤、A2和认知之间的联系是有用的。我们使用了饮食和环境丰富的干预措施，以确定它们是否可以单独或联合改善认知功能。我们已经证明，抗氧化剂和线粒体辅助因素饮食干预改善了老年狗的学习能力，并在2.8年的时间内保持了认知功能。随着学习的改善，我们用蛋白质组学的方法观察到抗氧化剂治疗的狗体内A2减少，氧化损伤减少。我们进一步表明，行为丰富也可以改善认知，但这是通过非A2/斑块机制发生的，因为A2似乎不受影响。重要的是，单独使用抗氧化剂饮食或行为强化治疗的有益认知效果在结合使用时会进一步增强。目前，每种疗法的分子靶点以及两种疗法之间导致累加神经功能改善的交汇点尚未确定。这项应用的主要目标是利用最新可用的技术(Affymetrix犬类基因组阵列)，并利用这些相同动物的脑组织来进一步建立和绘制每种治疗和联合治疗改善认知效果的神经生物学机制。为了实现这些目标，提出了以下目标：(1)分析狗的颞顶皮质基因表达随年龄的变化；(2)分析在给予抗氧化剂丰富的饮食和行为丰富的一种或两种情况下，老年狗的基因表达变化。进一步了解这两种干预措施所涉及的途径可能会导致新的研究假设、治疗方法和结果衡量标准，这些可能直接转化为人类临床试验。公共卫生相关性：分析抗氧化剂饮食和行为强化干预在老年犬身上造成的基因表达变化，将使我们能够识别和优化改善正常衰老个体和阿尔茨海默病患者认知能力的新疗法。