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: 6299342
• 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: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6299342
• 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.

衰老与多种生物功能的逐渐衰退有关 功能，通常反映了对全系统生理的局部反应 变化。该计划项目的总体目标是调查 与年龄相关的生长激素下降及其导致的下降的影响 大脑中的胰岛素样生长因子 1 (IGF-1)。 IGF-1 等 其他生长因子，影响两者的生长和分化 神经元和微血管支持巨大的新陈代谢 神经组织内的需求。 IGF-1 的大幅减少发生于 衰老可能会导致神经元形态发生显着变化 大脑内的功能。减少的时间相关性 IGF-1水平与认知能力普遍下降有关，最近 观察到给老年动物施用外源性IGF-1 提高认知能力，使该因素成为重要的候选者 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育和维持 因此，与年龄相关的 IGF-1 水平下降会显着影响 神经元的结构和活动。实验是基于这个想法 与衰老相关的认知缺陷必​​定会导致，至少 部分来自与年龄相关的神经元结构变化和/或损失 调节和维持神经元连接和信号传导的能力。 研究 IGF-1 与神经元形态之间的具体关系 我们将量化与年龄相关的变化的程度和复杂性 皮质神经元树突状过程的变化，以及 新陈代谢和血管化，在明确的区域内 大脑皮层。我们将确定这些变化是否是由于 通过测试是否与年龄相关的 IGF-1 水平下降 被传递给老年动物的外源性IGF-1逆转，通过以下方法预防 维持衰老动物中的 IGF-1 水平，并由早期诱导 年轻成年动物中 IGF-1 的正常减少。最后，我们将检查 IGF-1 调节神经元结构的具体机制 通过测量 IGF-1 对发育树突的影响来发挥功能， 检查 IGF-1 与其他神经营养因子的相互作用 影响神经元生长和分化并量化效果 IGF-1 信号对钙稳态的影响，钙稳态是神经元的关键调节因子 发育和功能。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 调节这些变化的关键因素。