Modifying age-related changes in mouse neuroinflammation & functional behaviors

改变小鼠神经炎症的年龄相关变化

基本信息

批准号：
8061708
负责人：
STEPHEN J BONASERA
金额：
$ 58.77万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/8061708
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

项目摘要

DESCRIPTION (provided by applicant): 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 and immune mediators, and (2) exercise and environmental enrichment improve CNS functional reserve by delaying or diminishing differential expression of genes regulating immune and inflammatory processes. We propose a cross-sectional study of young, middle-aged, and 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, and properties (duration, frequency, etc.) of movement, feeding, and drinking bouts will be analyzed. Preliminary data find 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, and 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 and environmental enrichment increase CNS functional reserve. We will use similar measures of mouse behavior and 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, and may suggest important genetic targets for therapeutic manipulation. PUBLIC HEALTH RELEVANCE: Ultimately, it is anticipated that these data will provide important insight regarding the nature of aging processes in the brain, and may suggest important genetic targets for therapeutic manipulation.

描述（由申请人提供）：未来几十年将以美国人口的“老龄化”为标志。该国增长最快的人口群体是老年人，而在这个群体中，即“最年长的老年人”。这些趋势对我们当前的医疗实践提出了重大挑战。例如，与年龄相关的行为变化的根本原因仍未确定。该应用程序将通过测试以下假设来检查衰老与功能行为（饮食、活动）变化之间的关系：（1）小鼠功能行为的年龄相关变化与调节炎症和免疫介质的基因表达变化相关，以及（ 2）运动和丰富的环境通过延迟或减少调节免疫和炎症过程的基因的差异表达来改善中枢神经系统的功能储备。我们建议对年轻、中年和老年小鼠进行横断面研究。将使用最先进的系统来监控行为，该系统以可靠和自动化的方式对大型行为数据流进行精细分类。将分析整体行为的测量，包括昼夜节律、时间预算以及运动、进食和饮水次数的特性（持续时间、频率等）。初步数据发现这些措施的变化与人口老龄化中的变化类似。此外，将使用微阵列和 QT-PCR 方法评估下丘脑和额叶皮层的基因表达。差异表达的基因产物将根据基因目的进行分类。这将使我们能够测试观察到的行为是否与调节免疫反应的基因变化相关，而不是与调节活动、运动和摄入行为的基因变化相关。我们还将使用图论方法来识别衰老下丘脑中改变的特定代谢途径（例如 Atf3-Mapk8-Tlr2）。我们还提出了一项纵向研究，以测试包括运动和环境丰富在内的生活方式改变是否会增加中枢神经系统功能储备。我们将使用类似的小鼠行为和基因表达测量作为本研究的结果。最终，我们预计这些数据将提供有关大脑衰老过程本质的重要见解，并可能为治疗操作提供重要的遗传靶标。公共健康相关性：最终，预计这些数据将提供有关大脑衰老过程本质的重要见解，并可能为治疗操作提出重要的遗传目标。