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: 10222560
• 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/10222560
• 关键词: Address; Age; Age-associated memory impairment; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease patient; Astrocytes; Attention; Attenuated; Biology of Aging; Brain; CDKN2A gene; Cell Cycle; Cell Cycle Arrest; Cells; Cellular biology; Characteristics; Child; 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; Pharmacology; Phenotype; Prevention; Process; Public Health; Research; Role; Senile Plaques; Severities; Severity of illness; Short-Term Memory; Site; Tauopathies; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transgenic Mice; Tweens; United States National Institutes of Health; Work; age related; aging population; attenuation; base; cell type; chemokine; cytokine; defined contribution; disability; genetic approach; improved; innovation; interdisciplinary approach; man; mouse model; normal aging; novel; novel strategies; prevent; preventive intervention; relating to nervous system; 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 老年学是指在分子水平上用多学科的方法来理解-- 衰老相关的病理和衰老之间的关系。不幸的是，仍然有一些基本的知识 在涉及这些机制如何随着年龄的增长易患无数疾病方面存在差距，包括 神经退行性疾病(ND)，如阿尔茨海默病(AD)。这种缺乏理解力代表着一种信号-- 这是一个重要的问题，因为在认识到这一点之前，预防或减轻这种损害的干预措施的发展 胆化症将继续是遥不可及的。衰老细胞(SNC)随着年龄的增长而积累，并在 与年龄相关的病理，并已被证明积极推动组织恶化。就像移除这些 细胞对衰老和寿命有很大的好处，这些细胞特别吸引人-- 测试老年科学假说的日期--该假说认为，降低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疾病。该实验室的长期目标是利用SNC许可作为一种治疗方法- 治疗各种年龄相关疾病的策略，包括阿尔茨海默病。具有让人想起Senes的特征的细胞- 因此，在死后AD患者中观察到了这种情况，因此这项应用的总体目标是 确定从已建立的ND模型中消除SNC是否可以减轻疾病的严重性。中央高铁- 假说是SNC积极推动疾病进程，移除这些细胞将预防或延缓AD 进展和严重程度。这一假设是在未发表的初步数据的基础上提出的 在本申请书所包括的申请人的实验室中生产。建议进行这项研究的理由是 一旦知道了大脑中特定细胞类型的衰老如何影响病理，就可以测试它是否 SNCs的新的药理调节和/或它们的作用影响疾病的过程。指导原则 强大的初步数据，将通过追求两个具体目标来检验假设：1)建立治疗- ND中SNC清除的TIC潜力；以及2)评估减弱的SNC积聚对ND和正常的影响 认知老化。在第一个目标下，将在已建立的疾病中使用各种SNC消除方法来 使用在申请者实验室建立的可行的新的小鼠模型来减轻严重性。在.之下 第二个目标是防止特定细胞类型的衰老，以确定这是如何影响疾病本身的。 Verity和SNC将从老年小鼠的基因中移除，以确定这是否会影响认知。美联社- 在申请人看来，Proach是创新的，因为它通过完全利用 通过调制SNCs来抵消ND的新方法。这项拟议的研究意义重大，因为它 将解决ND中有关SNC的关键基本问题，并测试以SNC为目标是否是潜在的治疗方法 针对这种疾病的治疗策略。这些知识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，而且还用于治疗或预防人类各种与年龄有关的疾病。