Growth Hormone & IGF-1 in CNS and Cerebrovascular Aging

生长激素

• 批准号: 7498134
• 负责人: William Edmund Sonntag
• 金额: $ 4.32万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-11 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7498134
• 关键词: Accounting; Address; Adult; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Animal Model; Animals; Appendix; Architecture; Behavioral; Blood - brain barrier anatomy; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain region; Breeding; Cells; Cerebrum; Chromosome Pairing; Condition; Disease; Doctor of Philosophy; Elderly; Elements; Endocrine; Funding; Genetic; Glutamate Receptor; Hippocampus (Brain); Hormones; Impaired cognition; Impairment; Inflammation; Infusion procedures; Insulin-Like Growth Factor I; Investigation; Learning; Left; Literature; Liver; Longevity; Mammals; Mediating; Memory; Metabolic; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neuroglia; Neurons; Numbers; Oxidative Stress; Peripheral; Physiological; Pituitary Gland; Plasma; Predisposition; Publishing; Rattus; Regulation; Reporting; Research Personnel; Rest; Rodent; Role; Seminal; Short-Term Memory; Silicon Dioxide; Somatomedins; Somatotropin; Synapses; Testing; Tissues; Vascular Dementia; age related; aging brain; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; angiogenesis; base; capillary; cerebrovascular; cognitive function; density; design; functional decline; glucose metabolism; growth hormone deficiency; healthy aging; hormone deficiency; lateral ventricle; neurogenesis; neuronal survival; novel; paracrine; prevent; programs; relating to nervous system; repaired; research study; senescence; synaptic function

This application is a competing continuation of a Program Project entitled 'Growth Hormone & IGF-1 in CNS and CerebrovascularAging'. The project is based on several key findings indicating that the progressive decline in plasma growth hormone and IGF-1 throughout the lifespan not only has an important effect on aging of peripheral tissues but that decreases in the levels of these hormones contribute to a decline in cognitive function. We hypothesize that the age-related cognitive decline results from a loss of growth hormone/IGF-1 dependent factors and/or inability to compensate for such a loss. Our proposed continued investigation into the role of growth hormone and IGF-1 deficiencies on brain aging includes three projects supported by Administration and Animal Cores. Project 1 is based on previously published seminal findings and preliminary studies that plasma growth hormone and IGF-1 are key regulators of vascular density, vascular reactivity and blood flow and hypothesizes that deficiencies in growth hormone and IGF-1 result in a mismatch between blood flow and metabolic demand in specific brain regions. Project 2 focuses on the role of growth hormone/IGF-l in regulating cell turnover in the aging brain and will assess whether the growth hormone/IGF-1 axis is a critical regulator of the replacement of both neurons and glia, sand that deficiency of these hormones result in increased oxidative stress and inflammation resulting in functional decline and a decreased ability to prevent and repair damage in the CNS. Project 3 is based on our findings that subunit levels of NMDA and AMPA types of glutamate receptors decrease with age in the rodent hippocampus and that IGF-1 infusion into the lateral ventricles increases synaptic complexity. Proposed studies will investigate age-related changes in the synaptic distribution of NMDA and AMPA subunits and their association with brain levels of IGF-1. An extremely novel aspect of this application is that the projects will incorporate an animal model of adult-onset growth hormone deficiency. This model will permit us to evaluate the specific actions of growth hormone and IGF-1 apart from pathologicalor secondary age-related changes within the CNS. The proposed studies will address key questions of the relationship between endocrine and microvascular changes and the neural substrates that contribute to cognitive decline, vascular dementia and increased susceptibility to diseases commonly observed in the elderly, including Alzheimer's disease.

此申请是一个竞争延续的计划项目题为“生长激素和IGF-1在中枢神经系统 和脑血管老化。该项目是基于几个关键的调查结果表明， 血浆生长激素和IGF-1在整个生命周期中的下降不仅对 外周组织的老化，但这些激素水平的下降有助于降低 认知功能我们假设与年龄相关的认知能力下降是由于生长的丧失 激素/IGF-1依赖因子和/或不能补偿这种损失。我们的建议继续 关于生长激素和IGF-1缺乏对大脑衰老的作用的研究包括三个项目 由管理和动物核心支持。项目1是基于以前发表的开创性发现 以及血浆生长激素和IGF-1是血管密度的关键调节因子的初步研究， 血管反应性和血液流动，并假设生长激素和IGF-1的缺乏导致 血液流动和特定大脑区域的代谢需求之间的不匹配。项目2侧重于角色 生长激素/IGF-1在调节衰老大脑细胞周转中的作用，并将评估生长激素/IGF-1是否 激素/IGF-1轴是神经元和神经胶质替代关键调节因子， 这些激素导致氧化应激和炎症增加，导致功能下降， 预防和修复CNS损伤的能力下降。项目3基于我们的发现， 在啮齿动物海马中，NMDA和AMPA型谷氨酸受体的水平随着年龄的增长而降低， IGF-1注入侧脑室增加了突触的复杂性。拟议的研究将调查 NMDA和AMPA亚单位突触分布的年龄相关变化及其与 IGF-1的水平。这个应用程序的一个非常新颖的方面是，项目将包含一个 成年发病生长激素缺乏症的动物模型。该模型将允许我们评估特定的 生长激素和IGF-1的作用，除了病理或继发性年龄相关的变化， CNS。拟议的研究将解决内分泌和 微血管变化和神经基质，有助于认知能力下降，血管性痴呆和 增加对老年人常见疾病的易感性，包括阿尔茨海默病。