Effects of Aging on Blood Vessels in the Cerebellar Vermis

衰老对小脑蚓部血管的影响

• 批准号: 9895600
• 负责人: Kunlin Jin
• 金额: $ 18.6万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895600
• 关键词: Accident and Emergency department; Affect; Age; Aging; Anterior; Attenuated; Biological Process; Blood Vessels; Blood Volume; Blood flow; Brain; Brain region; Cell Death; Cells; Cerebellar Diseases; Cerebellar vermis structure; Cerebellum; Cerebrovascular Circulation; Cerebrum; Degenerative Disorder; Diffusion Magnetic Resonance Imaging; Disease; Elderly; Endothelium; Equilibrium; Functional disorder; Gait; Glutathione; Goals; Health; Hippocampus (Brain); Human; Impairment; Individual; Inferior; Knowledge; Lateral; Lead; Lobe; Lobule; Locomotion; Microcirculation; Molecular; Motor; Motor Cortex; Mus; Nature; Nerve Degeneration; Neuronal Dysfunction; Neurons; Olives - dietary; Outcome; Oxidation-Reduction; Oxidative Stress; Persons; Pontine structure; Posture; Prefrontal Cortex; Purkinje Cells; Research; Risk; Role; SIRT1 gene; Severities; Statistical Data Interpretation; Structure; Testing; Tissues; Vascular Diseases; Vascular System; Work; age difference; age effect; age related; aged; aging brain; area striata; entorhinal cortex; experimental study; falls; human old age (65+); imaging study; improved; injury-related death; motor control; motor deficit; motor disorder; neuron loss; oxidative damage; senescence; white matter

Abstract Aging is a fundamental biological process accompanied by a general decline in tissue function and increased risk for many diseases. Indeed, decline in fine motor control, gait and balance is among the most important health problems in the elderly. Although the mechanism underlying cerebellar dysfunction is unclear, compelling evidence indicate that when the cerebellum ages, it starts to shrink in volume as a whole in the mid-fifties of humans. Looking particularly at the lobules as a whole, the anterior lobules (vermis) that control bodily posture and locomotion are most significantly affected by aging, but not the lateral portions of the cerebellum. It is well-known that aging-related structural and functional disturbances in the macro- or microcirculation of the brain lead to brain degeneration and dysfunction. However, whether aging impairs vascular structure and function of cerebellum is largely unknown. Our preliminary study showed that the number and volume of blood vessels were selectively reduced in vermis of cerebellum in aged mice, along with increased glutathione redox state, but the hippocampus was not affected. Thus, our central hypothesis is that: aging selectively impairs the vascular structure and function in vermis of cerebellum, which, in turn, increase oxidative damage in these regions, leading to neuronal dysfunction or loss and motor deficits. Our SPECIFIC AIM is to (1) determine whether aging selectively impairs vascular structure and function in the vermis of cerebellum, compared to other cerebellar and cerebral regions. (2) Determine whether aging increases oxidative stress and neurodegeneration in the vermis of cerebellum, compared to other cerebellar and cerebral regions. (3) Explore whether improved cerebral blood flow via increase of endothelial NAD+-SIRT1 activity reduces oxidative stress and attenuates neurodegeneration in the vermis of cerebellum and improve age-related cerebellar motor dysfunction. The rationale for the proposed research is that successful completion of the proposed experiments will provide missing, fundamental knowledge regarding the impact of the aging on vessel structure and function, and potential mechanisms underlying motor dysfunction in elderly.

抽象的 衰老是一个基本的生物过程，伴随着组织功能的普遍下降和 增加许多疾病的风险。事实上，精细运动控制、步态和平衡能力的下降是其中之一 老年人最重要的健康问题。尽管小脑的机制 功能障碍尚不清楚，令人信服的证据表明，当小脑衰老时，它开始萎缩 整个体积在人类五十年代中期。特别是从整个小叶来看， 控制身体姿势和运动的前小叶（蚓部）受以下因素影响最显着： 衰老，但小脑的外侧部分却没有衰老。众所周知，与衰老相关的结构和 大脑宏观或微循环的功能紊乱会导致大脑退化和 功能障碍。然而，衰老是否会损害小脑的血管结构和功能，目前尚无定论。 未知。我们的初步研究表明，血管的数量和体积是选择性的 老年小鼠小脑蚓部减少，谷胱甘肽氧化还原状态增加，但 海马体不受影响。因此，我们的中心假设是：衰老选择性地损害 小脑蚓部的血管结构和功能，进而增加小脑蚓部的氧化损伤 这些区域，导致神经元功能障碍或损失和运动缺陷。我们的具体目标是 (1) 确定衰老是否选择性损害小脑蚓部的血管结构和功能， 与其他小脑和大脑区域相比。 (2)确定衰老是否增加氧化 与其他小脑和大脑相比，小脑蚓部的应激和神经变性 地区。 (3)探讨是否通过增加内皮NAD+-SIRT1来改善脑血流量 活性可减少氧化应激并减轻小脑蚓部的神经退行性变 改善与年龄相关的小脑运动功能障碍。拟议研究的理由是 成功完成拟议的实验将提供缺失的基础知识 关于衰老对血管结构和功能的影响及其潜在机制 老年人运动功能障碍。