EFFECT OF AGE AND IGF-1 ON NEURONAL STRUCTURE AND FUNCTION

年龄和 IGF-1 对神经元结构和功能的影响

• 批准号: 6098497
• 负责人: DAVID RAY RIDDLE
• 金额: $ 15.51万
• 依托单位: WAKE FOREST UNIVERSITY
• 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 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098497
• 关键词: aging; biological signal transduction; brain metabolism; brain subcortex; calcium ion; cell differentiation; cell growth regulation; cerebrovascular system; cognition; dendrites; developmental neurobiology; electrophysiology; genetically modified animals; gonadotropin releasing factor; growth hormone releasing hormone; homeostasis; hormone regulation /control mechanism; insulinlike growth factor; laboratory rat; microcapsule; neural degeneration; neurons; neurotrophic factors; somatotropin; tissue /cell culture

Aging is associated with progressive declines in a variety of biological functions, often reflecting local responses to system-wide physiological changes. The overall goal of this Program Project is to investigate the effects of the age-related decline in growth hormone and resultant decline in insulin-like growth factor 1 (IGF-1) on the brain. IGF-1, like several other growth factors, influences the growth and differentiation of both neurons and the microvasculature that supports the tremendous metabolic demand within neural tissue. The large decrease in IGF-1 that occurs with senescence is likely to result in significant changes in neuronal form and function within the brain. The temporal correlation of the decrease in IGF-1 levels with a general decline in cognitive abilities, and the recent observation that administration of e exogenous IGF-1 to aged animals increases cognitive abilities, makes the factor an important candidate for further study. This project will test the hypothesis that IGF-1 influences the development and maintenance of neuronal architecture and metabolism such that the age-related decrease in IGF-1 levels significantly affects neurons structure and activity. The experiments are predicated on the idea that the cognitive deficits associated with aging must result, at least in part, from an age-associated change in neuronal architecture and/or a loss in ability to regulate and maintain neuronal connectivity and signaling. To examine the specific relationship between IGF-1 and neuronal form and function we will quantify age-related changes in the extent and complexity of dendritic processes of cortical neurons, as well as changes in metabolism and vascularization, within well-defined regions of the cerebral cortex. We will determine whether those changes are the result of the age-related decrease in IGF-1 levels by testing whether they are reversed by exogenous IGF-1 delivered to aged animals, prevented by maintaining IGF-1 levels in aging animals, and elicited by an earlier than normal decrease in IGF-1 in young adult animals. Finally, we will examine specific mechanisms by which IGF-1 may regulated neuronal structure and function by measuring the effects of IGF-1 on developing dendrites, examining the interaction of IGF-1 with other neurotropic factors that influence neuronal growth and differentiation and quantifying the effects of IGF-1 signaling on calcium homeostasis, a key regulator of the neuronal development and function. These studies will provide a greater understanding of the effects of age on the brain and of the role of one critical factor in regulating those changes.

衰老与多种生物学指标的进行性下降有关。 功能，通常反映对系统范围生理反应的局部反应 改变。本计划项目的总体目标是调查 与年龄相关的生长激素下降和由此导致的下降的影响 大脑中的胰岛素样生长因子-1(IGF-1)。IGF-1，就像几个 其他生长因素，影响两者的生长和分化 神经元和支持巨大代谢的微血管系统 神经组织内的需求。胰岛素样生长因子-1的大幅下降与 衰老可能导致神经元形态和功能的显著变化 在大脑中发挥作用。年增长率下降的时间相关性 认知能力普遍下降的IGF-1水平，以及最近 老年动物应用外源性胰岛素样生长因子-1的观察 提高认知能力，使该因素成为重要的候选因素 进一步研究。该项目将检验IGF-1影响的假设 神经元结构和新陈代谢的发展和维持 因此，与年龄相关的IGF-1水平的下降显著影响 神经元的结构和活性。这些实验是以这样的想法为前提的 与衰老相关的认知缺陷肯定会导致，至少在 部分原因是与年龄相关的神经元结构改变和/或丢失 调节和维持神经元连接和信号的能力。 探讨胰岛素样生长因子-1与神经元形态的特殊关系及 我们将量化与年龄相关的变化的程度和复杂性 大脑皮层神经元的树突状突起，以及 新陈代谢和血管形成，在明确界定的区域 大脑皮层。我们将确定这些变化是否是 通过测试IGF-1水平是否随年龄增长而下降 通过将外源性IGF-1传递给老年动物来逆转，通过 在衰老动物中维持IGF-1水平，并由早于 幼年成年动物体内IGF-1的正常下降。最后，我们将检查 胰岛素样生长因子-1调节神经元结构和功能的具体机制 通过测量IGF-1对树突发育的影响来发挥作用， 检测IGF-1与其他神经营养因子的相互作用 对神经元生长分化的影响及其量化效应 IGF-1信号转导对神经元钙稳态的关键调节作用 发展和功能。这些研究将提供更大的 了解年龄对大脑的影响以及年龄对大脑的作用 监管这些变化的关键因素。