Vervet Research Colony as a Biomedical Resource

作为生物医学资源的黑长尾黑长尾猴研究群体

• 批准号: 10119382
• 负责人: Matthew Jorgensen
• 金额: $ 35.77万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10119382
• 关键词: Administrative Supplement; African Green Monkey; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-42; Amyloid beta-Protein; Animals; Biological Markers; Biomedical Research; Brain; CCL2 gene; Caribbean region; Cerebrum; Cognitive; Cognitive deficits; Communities; Data; Deposition; Disease; Drowsiness; Elderly; Future; Genetic Transcription; Glucose; Goals; Human; Impaired cognition; Impairment; Insulin Resistance; Lead; Longitudinal Studies; Macaca mulatta; Mediating; Metabolic; Modeling; Mus; Nerve Fibers; Non-Insulin-Dependent Diabetes Mellitus; Performance; Peripheral; Population; Prospective Studies; Reporting; Research; Resources; Rest; Retina; Risk; Senile Plaques; Short-Term Memory; Sleep; Sleep Fragmentations; Sleep Wake Cycle; Sleep disturbances; Testing; Therapeutic Intervention; Thick; Thinness; Time; Tissue Banks; Type 2 diabetic; age difference; age related; biomedical resource; brain volume; clinical phenotype; cognitive function; cognitive performance; data warehouse; executive function; genetic pedigree; improved; middle age; motor deficit; neuroimaging; neuroimaging marker; neuropathology; new therapeutic target; nonhuman primate; novel; pathogen; regional atrophy; response; retinal nerve fiber layer; sleep quality; sleep quantity; tau aggregation; tau-1; translational model; translational study; vervet

PROJECT SUMMARY This application is submitted in response to NOT-AG-20-008 Alzheimer's-focused administrative supplements as a supplement to P40-OD010965 the Vervet Research Colony as a Biomedical Resource (VRC). The VRC is a national biomedical research resource mandated to provide the research community with access to pedigreed, genomically-sequenced, pathogen-free Caribbean-origin vervets/African green monkeys (Chlorocebus aethiops sabaeus). Vervets are increasingly recognized as a valuable NHP model for Alzheimer’s disease (AD). Vervets have age-related brain changes similar to humans including increases in Aβ plaque burden, cognitive and motor deficits, and changes in CSF AD biomarkers and changes with age in cortical transcription profiles. Also like humans, greater plaque and paired helical filament tau (phf-tau) burden are associated with reductions in brain volumes and cerebral glucose utilization. Like humans, some vervets develop insulin resistance with age that may progress to type 2 diabetes accompanied by decreased CSF Aβ42/Aβ40. Age-related sleep, and sleep–related cognitive function have not been studied in vervets and there are only two reports in other NHPs. In humans, poor sleep impairs cognitive functioning. While quantity and quality of sleep decline with age, these decrements are exaggerated in AD. Poor sleep and daytime somnolence are associated with greater AD neuropathology as indicated by CSF and neuroimaging biomarkers. Prospective studies suggest that poor sleep increases subsequent risk of AD. However, in mice, Aβ plaque deteriorates the sleep-wake cycle suggesting that Aβ and sleep may have a bidirectional relationship. Sleep disturbances are associated with insulin resistance, and increase risk for type 2 diabetes. Peripheral insulin resistance increases risk for cognitive impairment and AD. However, type 2 diabetics have poor sleep suggesting these relationships also may be bidirectional. Determination of age-related changes in sleep, and their relationships with cognitive performance, insulin resistance, and AD risk may lead to new targets for therapeutic intervention. Our overall goal is to develop the vervet as a model in which to identify novel targets and evaluate therapies for the detrimental effects of poor sleep on cognitive function, insulin resistance, and AD-like neuropathology. Our specific aims are to determine, in middle-aged and elder vervets, age differences in sleep quantity and quality, and whether poor sleep is associated with poor cognitive function, AD neuroimaging and CSF biomarkers, or insulin resistance, and if age mediates these relationships. The results of this study will provide a NHP model and pilot data to support subsequent applications to determine the temporal order of emergence of these disorders in a longitudinal study, whether therapeutic intervention on sleep improves cognitive and metabolic function, and CSF and neuroimaging biomarkers, and identify novel therapeutic targets to intervene on the detrimental effects of poor sleep on cognitive function, insulin resistance, and AD-like neuropathology.

项目摘要 本申请是为了回应NOT-AG-20-008以阿尔茨海默病为重点的行政补充而提交的 作为P40-OD 010965的补充，Vervet研究菌落作为生物医学资源（VRC）。VRC是 一个国家生物医学研究资源，授权为研究界提供访问 纯种、基因组测序、无病原体的加勒比海起源长尾猴/非洲绿色猴 （Chlorocebus aethiops sabaeus）。长尾小蜂越来越被认为是一种有价值的NHP模型， 阿尔茨海默病（AD）。黑长尾猴与人类相似的与年龄相关的大脑变化包括Aβ的增加 斑块负荷、认知和运动缺陷、CSF AD生物标志物的变化以及 皮质转录谱也像人类一样，更大的斑块和配对螺旋丝tau蛋白（PHF-tau）负担 与脑容量和脑葡萄糖利用的减少有关。像人类一样，一些长尾猴 随着年龄的增长出现胰岛素抵抗，可能进展为2型糖尿病伴CSF减少 Aβ42/Aβ40。与睡眠相关的睡眠，以及与睡眠相关的认知功能尚未在黑尾长尾猴中进行过研究， 在其他国家卫生计划中只有两份报告。在人类中，睡眠不足会损害认知功能。数量和 睡眠质量随着年龄的增长而下降，这些下降在AD中被夸大。睡眠和白天不好 如CSF和神经影像学所示，嗜睡与更严重的AD神经病理学相关 生物标志物。前瞻性研究表明，睡眠不好会增加随后患AD的风险。然而，在小鼠中， Aβ斑块使睡眠-觉醒周期恶化，提示Aβ与睡眠可能存在双向调节作用。 关系睡眠障碍与胰岛素抵抗有关，并增加2型糖尿病的风险。 外周胰岛素抵抗增加认知障碍和AD的风险。然而，2型糖尿病患者 睡眠不佳表明这些关系也可能是双向的。年龄相关变化的测定 睡眠，以及它们与认知能力、胰岛素抵抗和AD风险的关系，可能会导致新的 治疗干预的目标。我们的总体目标是将长尾猴发展为一种模型， 新的目标和评估治疗睡眠不良对认知功能的不利影响，胰岛素 抵抗和AD样神经病理学。我们的具体目标是确定，在中年和老年人 睡眠数量和质量的年龄差异，以及睡眠不好是否与认知能力差有关。 功能，AD神经影像学和CSF生物标志物，或胰岛素抵抗，以及年龄是否介导这些关系。 本研究的结果将提供一个NHP模型和试点数据，以支持后续的应用， 在纵向研究中确定这些疾病出现的时间顺序， 对睡眠的干预改善了认知和代谢功能，以及CSF和神经影像学生物标志物， 确定新的治疗靶点，以干预睡眠不良对认知功能的有害影响， 胰岛素抵抗和AD样神经病理学。