The Relationship between Inflammation and Cognition in a Monkey Model of Human Aging

人类衰老猴子模型中炎症与认知的关系

• 批准号: 10121323
• 负责人: SEAN D SULLIVAN
• 金额: $ 33.88万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-10 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10121323
• 关键词: 16S ribosomal RNA sequencing; Adult; Affect; Age; Aging; Alveolar Bone Loss; Alzheimer' s Disease; American; Anatomy; Animals; Area; Attenuated; Biological Assay; Blood; Buffaloes; Chronic; Cognition; Communicable Diseases; Data; Dementia; Dental; Dentition; Diabetes Mellitus; Disease; Elderly; Epithelial; Epithelium; Exhibits; Funding; Future; Gene Expression Profile; Gingiva; Gingival Crevicular Fluid; Goals; Grant; Heart Diseases; Height; Hippocampus (Brain); Human; Immunology; Impaired cognition; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Liquid substance; Macaca mulatta; Measures; Medial; Memory; Modeling; Monkeys; Mouth Diseases; Mus; Neurobiology; Neurofibrillary Tangles; Oral; Oral health; Pathology; Patients; Pattern; Performance; Periodontal Diseases; Periodontium; Pilot Projects; Play; Prefrontal Cortex; Primates; Proteins; Research; Risk Factors; Saliva; Sample Size; Sampling; School Dentistry; Scientist; Senile Plaques; Serum; Short-Term Memory; Signal Transduction; Sirolimus; Staging; Standardization; Structure; Systems Biology; Temporal Lobe; Therapeutic; Tissues; Tooth Loss; Tooth structure; Training; Translations; Universities; Visual; Washington; age effect; age related; aged; analog; association cortex; base; bone; cognitive neuroscience; cognitive performance; cognitive testing; cost estimate; cytokine; dysbiosis; economic cost; executive function; health assessment; healthy aging; high risk; human model; human old age (65+); immune activation; inflammatory marker; insight; mTOR Inhibitor; mTOR inhibition; memory recognition; microbial community; normal aging; oral microbiome; prefrontal lobe; programs; standard measure; tool; translational medicine; translational neuroscience; treatment effect

ABSTRACT This application is for a supplement to the P51 Primate Research Center Grant that supports the Washington National Primate Research Center. This supplement will be used to conduct a 1-year pilot study towards establishing a new research program to characterize the association between inflammation and age-related changes in cognitive performance and oral health in monkeys (rhesus macaques). Monkeys provide a strong model for advancing our understanding of the neurobiology of human memory and executive function due to robust cross-species similarities in the anatomy and connectivity of the medial temporal lobe and prefrontal cortex. Accumulating evidence has suggested an association between cognitive impairment and systemic immune activation. Elevated serum levels of pro-inflammatory cytokines have been shown to be related to cognitive impairment, and this inflammation-cognition association has been demonstrated in otherwise healthy older individuals. Along with inflammation-cognition, inflammation-oral health association is also demonstrated in older individuals in the form of periodontal disease (PD), a chronic inflammatory oral disease affecting nearly 70% of U.S. adults over the age of 65 which leads to a dysbiotic oral microbiome, destruction of the gingival epithelium and periodontal bone with ultimately tooth loss. PD is also a major risk factor for several other age-related disorders, including heart disease and diabetes, and patients with chronic periodontal disease have a higher risk of developing dementia. We recently discovered that the specific mTOR inhibitor rapamycin caused a revertive shift of the old oral microbiome to be more similar to the young oral microbiome in mice, attenuated gingival and periodontal tissue inflammation, and reversed periodontal bone loss in old animals. Thus, the overarching goals of this proposal are to (1) determine whether elevated levels of pro-inflammatory cytokines are associated with cognitive decline, (2) establish the aged rhesus monkey as a model for naturally occurring periodontal disease, and (3) analyze the direct impact of mTOR inhibition on age-related oral and cognitive decline.

抽象的 此申请是对 P51 灵长类研究中心补助金的补充，该补助金支持 华盛顿国家灵长类动物研究中心。该补充品将用于进行为期 1 年的 旨在建立新研究计划的试点研究，以表征之间的联系 猴子认知能力和口腔健康的炎症和年龄相关变化 （恒河猴）。猴子为增进我们对生物的理解提供了一个强有力的模型 由于跨物种的强大相似性，人类记忆和执行功能的神经生物学 内侧颞叶和前额皮质的解剖结构和连接性。积累中 有证据表明认知障碍与系统免疫之间存在关联 激活。血清促炎细胞因子水平升高已被证明与 认知障碍，这种炎症与认知的关联已在 其他方面健康的老年人。除了炎症-认知、炎症-口腔健康 老年人中也以牙周病（PD）的形式证明了这种关联，牙周病是一种 慢性炎症性口腔疾病影响着近 70% 的美国 65 岁以上成年人， 导致口腔微生物群失调、牙龈上皮和牙周骨遭到破坏 最终导致牙齿脱落。 PD 也是其他几种与年龄相关的疾病的主要危险因素， 包括心脏病和糖尿病，慢性牙周病患者的患病率更高 患痴呆症的风险。我们最近发现特异性 mTOR 抑制剂雷帕霉素 导致旧口腔微生物组的恢复性转变，使其与年轻口腔微生物组更加相似 在小鼠中，减轻牙龈和牙周组织炎症，逆转牙周骨 老动物的损失。因此，该提案的总体目标是（1）确定是否 促炎细胞因子水平升高与认知能力下降相关，(2) 建立 将老年恒河猴作为自然发生的牙周病的模型，以及（3）分析 mTOR 抑制对年龄相关的口腔和认知能力下降的直接影响。