Protective factors and mechanisms

保护因素和机制

• 批准号: 10689333
• 负责人: Doo Yeon Kim
• 金额: $ 102.68万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10689333
• 关键词: 3-Dimensional; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Area; Astrocytes; Autopsy; Biological; Blood; Brain; Brain Pathology; Brain region; Cell Line; Cell model; Cellular Assay; Centenarian; Code; Cognitive; Data; Dementia; Disease; Drug usage; Exposure to; Gene Frequency; Genes; Genetic; Goals; Human; Impaired cognition; Impairment; Life Expectancy; Measures; MicroRNAs; Microglia; Modeling; Molecular; Neuroglia; Neurons; Organoids; Pathway interactions; Pharmaceutical Preparations; Phenotype; Privatization; Process; Prosencephalon; RNA Sequences; Research; Resistance; Risk Factors; Serum; Spouses; Testing; Therapeutic; Tissues; Untranslated RNA; Validation; Variant; Work; abeta accumulation; age related; brain cell; candidate validation; circulating biomarkers; drug candidate; endophenotype; exome; genetic variant; induced pluripotent stem cell; microRNA biomarkers; molecular resilience; neural; neuroimaging; offspring; promote resilience; protective allele; protective factors; resilience; sex; transcriptome; transcriptome sequencing; transcriptomics

RADCO Project 2 Summary Much of cognitive impairment and dementia research has concentrated on disease mechanisms and targets for disrupting these. A compelling alternative approach is to delineate naturally occurring mechanisms of protection. Some centenarians remain cognitively intact despite an extreme exposure to the strongest risk factor for cognitive impairment and AD, aging. We hypothesize that these centenarians and some portion of their offspring have protective factors that lead to such resilience or in some cases, even resistance against cognitive decline and dementia. With the support of the Administrative, Phenotyping and Biosamples, and Neuroimaging Cores, and Project 1 (Resilience and Resistance Phenotypes), this 2nd project of the “Resistance/Resilience to AD in Centenarians and Offspring" (RADCO) study strives to discover factors and mechanisms protective against cognitive impairment, AD and other dementias. This project entails three related approaches: genetics (Aim 1), transcriptomic analyses (Aim 2), and 3D human neural-glial culture models of age-related brain pathology (Aim 3). Our goals are to 1) identify genetic variants and biological mechanisms of resilience/resistance in centenarian cognitive superagers, 2) predict mechanisms of cognitive resilience and validate candidate drugs that can enhance the resilience/resistance in human brain cells, and 3) establish induced pluripotent stem cells (iPSCs) and iPSC-derived 3D brain cell models of the centenarian superagers to test those mechanisms as well as discover and test others that could be exploitable for protective therapeutics.

RADCO项目2摘要 许多认知障碍和痴呆症的研究都集中在疾病机制上 和破坏这些的目标。另一种令人信服的方法是自然地描绘 保护机制的出现。一些百岁老人的认知能力仍然完好无损， 极度暴露于认知障碍和AD的最强风险因素，衰老。我们 假设这些百岁老人和他们后代的某些部分具有保护因素 导致这种恢复力，或者在某些情况下，甚至抵抗认知能力下降， 痴呆在管理、表型分析和生物样品部门的支持下， 神经影像核心，和项目1（弹性和阻力表型），这第二个项目的 “百岁老人和后代对AD的抵抗力/恢复力”（RADCO）研究致力于 发现对认知障碍、AD和其他疾病的保护因素和机制 痴呆症该项目涉及三个相关的方法：遗传学（目标1），转录组学 分析（目的2）以及年龄相关脑病理学的3D人类神经胶质细胞培养模型（目的 （3）第三章。我们的目标是：1）识别遗传变异和弹性/抗性的生物学机制 在百岁认知超级老人中，2）预测认知弹性的机制，并验证 可以增强人脑细胞的弹性/抵抗力的候选药物，以及3）建立 百岁老人的诱导多能干细胞（iPSC）和iPSC衍生的3D脑细胞模型 超级老人测试这些机制，以及发现和测试其他可能被利用 用于保护性治疗。