Modifying age-related changes in mouse neuroinflammation & functional behaviors

改变小鼠神经炎症的年龄相关变化

• 批准号: 8278555
• 负责人: STEPHEN J BONASERA
• 金额: $ 58.52万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278555
• 关键词: Address; Aerobic Exercise; Affect; Age; Aged, 80 and over; Aging; Aging-Related Process; Behavior; Behavior Therapy; Behavioral; Biological Response Modifiers; Brain; Budgets; Cell Culture Techniques; Cell physiology; Cells; Circadian Rhythms; Country; Cross-Sectional Studies; Data; Eating; Eating Behavior; Elderly; Exercise; Facies; Feeding behaviors; Fluorescence-Activated Cell Sorting; Frequencies; Gene Expression; Genes; Genetic; Graph; Gray unit of radiation dose; Health; Human; Hypothalamic structure; Immune; Immune response; Immunity; Impairment; In Situ Hybridization; Individual; Inflammation; Inflammation Mediators; Inflammatory; Intervention; Life; Longitudinal Studies; Measures; Medical; Metabolic; Metabolic Pathway; Methods; Microglia; Monitor; Movement; Mus; Nature; Nerve Degeneration; Ontology; Outcome; Persons; Physical activity; Population; Process; Property; Proteins; Quality of life; Stream; System; T-Lymphocyte; Testing; Time; Tissue-Specific Gene Expression; Tissues; Toll-like receptors; United States; Water consumption; Work; activating transcription factor 3; age related; aged; cohort; drinking; environmental enrichment for laboratory animals; experience; feeding; frontal lobe; functional status; immunocytochemistry; improved; inhibitor/antagonist; insight; lifestyle intervention; middle age; mouse model; neuroinflammation; overexpression; prevent; theories; therapeutic target; trend

The coming decades will be marked by a "graying" of the United States population. The most rapidly growing demographic group in the country is that of elderly persons, and within this group, that of the "oldest old." These trends pose significant challenges to our current medical practice. For example, the underlying causes of age-related behavioral changes remain undetermined. This application will examine the relationship between aging and changes in functional behaviors (eating, drinking, activity) by testing the hypotheses that (1) Age-related changes in mouse functional behaviors correlate with changes in gene expression regulating inflammatory & immune mediators, and (2) Exercise & environmental enrichment improve CNS functional reserve by delaying or diminishing differential expression of genes regulating immune & inflammatory processes. We propose a cross-sectional study of young, middle-aged, & aged mice. Behaviors will be monitored using a state-of-the-art system that finely classifies large behavioral data streams in a reliable and automated fashion. Measures of overall behavior, including those of circadian rhythm, time budget, & properties (duration, frequency, etc.) of movement, feeding, and drinking bouts will be analyzed. Preliminary data finds alterations in these measures similar to those seen in aging human populations. Additionally, gene expression in the hypothalamus and frontal cortex will be assessed using microarray and QT-PCR methods. Differentially expressed gene products will be classified by gene purpose. This will allow us to test whether observed behaviors correlate with changes in genes regulating immune responses rather than genes regulating activity, movement, & ingestive behaviors. We will also use graph-theory approaches to identify specific metabolic pathways (e.g., Atf3-Mapk8-Tlr2) altered in the aging hypothalamus. We also propose a longitudinal study to test whether lifestyle modifications including exercise & environmental enrichment increase CNS functional reserve. We will use similar measures of mouse behavior & gene expression as outcomes in this study. Ultimately, we anticipate that these data will provide important insight regarding the nature of aging processes in the brain, & may suggest important genetic targets for therapeutic manipulation.

未来几十年，美国人口将出现“老龄化”。最快的 该国人口中老年人群体不断增加，在这一群体中，“最年长者”群体也在不断增加。 老了“这些趋势对我们目前的医疗实践提出了重大挑战。例如，底层 与年龄有关的行为变化的原因仍然没有确定。此应用程序将检查 通过测试衰老与功能行为（饮食、活动）变化之间的关系 假设（1）小鼠功能行为中与神经元相关的变化与 调节炎症和免疫介质的基因表达，和（2）运动和环境 富集通过延迟或减少 调节免疫和炎症过程的基因。我们建议对年轻人进行横断面研究， 中年老鼠和老年老鼠行为将被监测使用一个国家的最先进的系统， 以可靠和自动化的方式处理大型行为数据流。整体行为指标，包括 昼夜节律，时间预算和属性（持续时间，频率等）运动，进食， 将分析饮酒发作。初步数据发现，这些措施的变化类似于 人口老龄化此外，下丘脑和额叶皮层的基因表达将被 使用微阵列和QT-PCR方法评估。差异表达的基因产物将被分类 基因的目的这将使我们能够测试观察到的行为是否与基因的变化相关 调节免疫反应，而不是调节活动，运动和摄食行为的基因。我们 还将使用图论方法来识别特定的代谢途径（例如，Atf 3-Mapk 8-Tlr 2）改变 在老化的下丘脑中。我们还提出了一项纵向研究，以测试生活方式的改变是否 包括运动和环境丰富增加中枢神经系统的功能储备。我们将使用类似的 小鼠行为和基因表达的测量作为本研究的结果。最终，我们预计， 这些数据将提供关于大脑老化过程本质的重要见解， 重要的基因治疗靶点。