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: 7853928
• 负责人: STEPHEN J BONASERA
• 金额: $ 57.33万
• 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/7853928
• 关键词: Affect; Age; Age-Months; Aged, 80 and over; Aging; Aging-Related Process; Arts; Astrocytes; Behavior; Behavior Therapy; Behavioral; Biological Assay; Biological Response Modifiers; Brain; Budgets; C57BL/6 Mouse; Categories; Circadian Rhythms; Corpus striatum structure; Country; Cross-Sectional Studies; Data; Eating Behavior; Elderly; Exercise; Feeding behaviors; Food; Frequencies; Gene Expression; Genes; Genetic; Genetic Processes; Goals; Graph; Gray unit of radiation dose; Home environment; Human; Hypothalamic structure; Immune; Immune response; Inflammatory; Ingestion; Intervention; Life; Life Style; Link; Locomotion; Longitudinal Studies; Measures; Mediating; Medical; Metabolic Pathway; Methods; Microglia; Modification; Monitor; Movement; Mus; Nature; Nervous System Physiology; Neuraxis; Neuroglia; Neurons; Ontology; Outcome; Pattern; Persons; Population; Process; Property; Proteins; Research; Stream; Subgroup; System; Testing; Time; Tissue-Specific Gene Expression; United States; Water; Work; age related; aged; base; cohort; drinking; environmental enrichment for laboratory animals; feeding; frontal lobe; immune function; immunocytochemistry; improved; insight; lifestyle intervention; middle age; neuroinflammation; public health relevance; theories; therapeutic development; therapeutic target; tool; trend

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“灰色”为标志。该国增长最快的人口群体是老年人，在这个群体中，是“最古老的老年人”。这些趋势对我们当前的医学实践构成了重大挑战。例如，与年龄相关的行为变化的根本原因尚不确定。该应用将通过测试（1）（1）与年龄相关的小鼠功能行为变化的假设与基因表达的变化相关的假设，以调节炎症和免疫介质的变化，（2）运动和环境丰富的疾病通过延迟或减小的基因的炎症来改善疾病的疾病，将其与基因表达的变化相关。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视行为，该系统以可靠和自动化的方式对大型行为数据流进行了细微的分类。将分析整体行为的衡量标准，包括昼夜节律，时间预算以及运动，进食和饮酒次数的属性（持续时间，频率等）的度量。初步数据发现这些措施的变化与人类衰老的人群相似。另外，将使用微阵列和QT-PCR方法评估下丘脑和额叶皮层中的基因表达。差异表达的基因产物将以基因目的进行分类。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的变化相关，而不是调节活性，运动和摄取行为的基因。我们还将使用图理论方法来识别衰老下丘脑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富集在内的生活方式修改是否会增加CNS功能储备。在这项研究中，我们将使用类似的小鼠行为和基因表达量度与结果。最终，我们预计这些数据将为大脑衰老过程的性质提供重要的见解，并可能暗示进行治疗操作的重要遗传靶标。公共卫生相关性：最终，预计这些数据将为大脑衰老过程的性质提供重要的见解，并可能暗示进行治疗操作的重要遗传靶标。