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.

项目概要 老年科学是指采用多学科方法在分子水平上理解以下关系： 不幸的是，在与衰老相关的病理学和衰老之间仍然存在一些基础知识。 在暗示这些机制如何随着年龄的增长而诱发多种疾病方面存在差距，包括 对阿尔茨海默病 (AD) 等神经退行性疾病 (ND) 的缺乏理解是一个标志。 这是一个严重的问题，因为在人们认识到这一点之前，需要制定干预措施来预防或减轻这种情况 衰老细胞（SnC）会随着年龄的增长以及在疾病部位的积累而继续无法实现。 与年龄相关的病理学，并已被证明可以积极驱动组织退化。 细胞对衰老和寿命有很大的有益影响，这些细胞是特别有吸引力的候选者 测试老年科学假设的日期，即减弱“衰老速度”可能会延缓神经退行性疾病 - es 和其他与年龄相关的条件。实验室的长期目标是利用 SnC 清除作为热疗法。 治疗多种与年龄相关的疾病（包括 AD）的治疗策略。 在死后 AD 患者中观察到了这种情况，因此本应用的总体目标是 确定从已建立的 ND 模型中消除 SnC 是否会减轻疾病的严重程度。 假设是 SnC 主动驱动疾病进程，去除这些细胞将预防或延缓 AD 该假设是根据未发表的初步数据提出的 本申请中包含的申请人实验室产生的研究的基本原理是。 一旦了解大脑中特定细胞类型的衰老如何影响病理学，就可以测试是否 SnC 的新药理调节和/或其作用影响疾病过程。 有了强有力的初步数据，该假设将通过追求两个具体目标来检验：1）建立治疗方法 ND 中 SnC 去除的抽动潜力；以及 2) 评估减弱的 SnC 积累如何影响 ND 和正常 在第一个目标下，将使用各种消除 SnC 的方法来治疗已确定的疾病。 使用申请人实验室中可行的新型小鼠模型来减轻严重程度。 第二个目标是防止特定细胞类型的衰老，以确定这如何影响疾病的发生 verity 和 SnC 将从老年小鼠身上进行基因去除，以确定这是否会影响认知。 申请人认为，该方法是创新的，因为它完全利用了一种方法来背离现状。 通过调制 SnC 来抵消 ND 的新方法这项研究意义重大，因为它。 将解决有关 ND 中 SnC 的关键基本问题，并测试针对 SnC 是否是一种潜在的热疗法 这种疾病的治疗策略将为变革性的临床干预铺平道路。 不仅用于治疗或预防新城疫，还用于治疗或预防广泛的人类年龄相关疾病。