Effects of senescence to AlzheimerâÂÂs disease pathology

衰老对阿尔茨海默病病理学的影响

• 批准号: 10670811
• 负责人: Darren Baker
• 金额: $ 39.75万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670811
• 关键词: Age; Age-associated memory impairment; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease patient; Astrocytes; Attention; Attenuated; Autopsy; Biology of Aging; Brain; CDKN2A gene; Cell Cycle; Cell Cycle Arrest; Cells; Cellular biology; Characteristics; Clinical; Cognition; Cognitive aging; Comprehension; Data; Deposition; Deterioration; Development; Disease; Disease Progression; Disease model; Elderly; Excision; Exhibits; Functional disorder; Geroscience; Goals; Growth Factor; Human; Impaired cognition; Impairment; Inflammatory; Intervention; Knowledge; Laboratories; Laboratory mice; Life; Longevity; Matrix Metalloproteinases; Methods; Microglia; Mission; Molecular; Mus; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Neurofibrillary Tangles; Outcome; Pathogenesis; Pathology; Patients; Phenotype; Prevention; Probability; Process; Public Health; Research; Role; Senile Plaques; Severities; Severity of illness; Short-Term Memory; Site; Tauopathies; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transgenic Mice; United States National Institutes of Health; Work; age related; age related neurodegeneration; aging population; attenuation; cell type; chemokine; cytokine; defined contribution; disability; genetic approach; improved; innovation; interdisciplinary approach; mouse model; neural; normal aging; novel; novel strategies; pharmacologic; prevent; preventive intervention; senescence; therapy development

Project Summary Geroscience refers to the multi-disciplinary approach to understand, at the molecular level, the relationship be- tween aging-associated pathologies and aging. Unfortunately, there continues to be a fundamental knowledge gap in implicating how these mechanisms predispose to a myriad of diseases with advancing age, including neurodegenerative diseases (ND) like Alzheimer’s disease (AD). This lack of comprehension represents a sig- nificant problem because, until it is recognized, development of interventions that prevent or attenuate this de- bilitating disease will continue to be unattainable. Senescent cells (SnCs) accumulate with age and at sites of age-related pathology and have been demonstrated to actively drive tissue deterioration. As removal of these cells has largely beneficial consequences for aging and lifespan, these cells are particularly attractive candi- dates to test the geroscience hypothesis that attenuated ‘rates of aging’ may delay neurodegenerative diseas- es and other age-related conditions. The long-term goal of the laboratory is to exploit SnC clearance as a ther- apeutic strategy for a variety of age-related diseases, including AD. Cells with features reminiscent of senes- cence have been observed in post mortem AD patients, therefore the overall objective in this application is to determine whether SnC elimination from established ND models attenuates disease severity. The central hy- pothesis is that SnCs actively drive disease processes and that removal of these cells will prevent or delay AD progression and severity. This hypothesis has been formulated on the basis of unpublished preliminary data produced in the applicants’ laboratory included in this application. The rationale for the proposed research is that once it is known how senescence of specific cell types in the brains impacts pathology, it can be tested if novel pharmacological modulations of SnCs and/or their effects influences the disease process. Guided by strong preliminary data, the hypothesis will be tested by pursuing two specific aims: 1) Establish the therapeu- tic potential of SnC removal in ND; and 2) Evaluate how attenuated SnC accumulation impacts ND and normal cognitive aging. Under the first aim, various methods of SnC elimination will be used in established disease to attenuate severity using novel mouse models established as feasible in the applicants’ laboratory. Under the second aim, senescence in specific cell types will be prevented to determine how this influences disease se- verity and SnCs will be genetically removed from geriatric mice to determine if this impacts cognition. The ap- proach is innovative, in the applicant’s opinion, because it departs from the status quo by utilizing an entirely novel approach to counteract ND through modulation of SnCs. The proposed research is significant, because it will address key fundamental questions about SnCs in ND and test whether targeting SnCs is a potential ther- apeutic strategy for this disease. This knowledge will pave the way towards transformative clinical interventions for treating or preventing not only ND, but also a broad spectrum of human age-related diseases.

项目摘要 老年科学是指多学科的方法来理解，在分子水平上，关系是- 与衰老相关的病理学和衰老之间的关系。不幸的是，我们仍然有一个基本的知识 在暗示这些机制如何随着年龄的增长而易患各种疾病方面存在差距，包括 神经退行性疾病（ND），如阿尔茨海默病（AD）。这种不理解是一种信号， 这是一个严重的问题，因为在认识到这一点之前，预防或减轻这种疾病的干预措施的发展， bilitating疾病将继续无法实现。衰老细胞（SnC）随着年龄的增长而积累，并在 年龄相关的病理学，并已被证明积极推动组织恶化。由于这些删除 细胞对衰老和寿命有很大的好处，这些细胞是特别有吸引力的糖果， 日期来测试老年科学假设，即衰减的“衰老率”可能会延迟神经退行性疾病- 以及其他与年龄有关的疾病。该实验室的长期目标是利用SnC清除作为治疗方法， 包括AD在内的各种年龄相关疾病的治疗策略。细胞的特征让人联想到衰老- 在AD患者死后观察到了这种情况，因此本申请的总体目的是 确定从已建立的ND模型中消除SnC是否减轻了疾病的严重程度。中央卫生- 假设是SnC积极驱动疾病进程，去除这些细胞将预防或延迟AD 进展和严重程度。这一假设是根据未发表的初步数据提出的 在本申请中包括的申请人的实验室中产生的。拟议研究的基本原理是 一旦知道大脑中特定细胞类型的衰老如何影响病理学，就可以测试， SnC的新的药理学调节和/或它们的作用影响疾病过程。指导 强有力的初步数据，该假设将通过追求两个具体目标进行测试：1）建立治疗， 2）评估减弱的SnC积累如何影响ND和正常 认知老化在第一个目标下，各种SnC消除方法将用于确定的疾病， 使用申请人实验室中可行建立的新型小鼠模型来减轻严重程度。下 第二个目标，将防止特定细胞类型的衰老，以确定这如何影响疾病本身， verity和SnCs将从老年小鼠中遗传去除，以确定这是否影响认知。该ap- 在申请人看来，该方法是创新的，因为它通过利用一种完全 通过SnCs的调制来抵消ND的新方法。这项研究意义重大，因为它 将解决关于ND中SnCs的关键基本问题，并测试靶向SnCs是否是一种潜在的治疗方法， 对这种疾病的治疗策略。这些知识将为变革性临床干预铺平道路 不仅用于治疗或预防ND，而且用于治疗或预防广谱的人类年龄相关疾病。