A geroscience approach for investigating resilience to SARS-CoV-2 pathology in mice with Alzheimer's disease

一种用于研究阿尔茨海默病小鼠对 SARS-CoV-2 病理学恢复能力的老年科学方法

• 批准号: 10197633
• 负责人: Martin C Darvas
• 金额: $ 54.84万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10197633
• 关键词: 2019-nCoV; Acarbose; Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-42; Biological Aging; Brain; COVID-19; Clinical; Combined Modality Therapy; Communicable Diseases; Composite Lesion; Crowding; Decontamination; Development; Disease; Drug Combinations; Elderly; Evaluation; Failure; Geroscience; Goals; Guidelines; Handwashing; Health; Impaired cognition; Individual; Infection; Intensive Care; Intervention; Lesion; Morbidity - disease rate; Mus; Neurons; Organ; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Phenylbutyrates; Physical Performance; Population; Predisposition; Procedures; Process; Risk; Risk Factors; SARS-CoV-2 exposure; SARS-CoV-2 infection; Sirolimus; Testing; Therapeutic; Tissues; Virus; age related; aged; anti aging; cohort; comorbidity; cytokine; design; dietary control; drug repurposing; improved; infection risk; mild cognitive impairment; mortality; mouse model; neuropathology; novel drug combination; parent grant; prevent; prophylactic; prototype; resilience; response; treatment effect

Abstract The parent grant for this supplement application is R01 AG067193, “A geroscience approach for treating Alzheimer's disease”. The supplement proposal is an extension of the parent grant and is titled “A geroscience approach for investigating resilience to SARS-CoV-2 pathology in mice with Alzheimers disease”. The extension is designed to look at the complications of COVID-19 in the presence of cognitive impairment and neuropathological lesions of Alzheimer's disease in an aging mouse model. This is translationally relevant because patients with cognitive impairment related to Alzheimer's disease (AD) are at increased risk for complications of SARS-CoV-2 infection. Several factors are involved including cognitive impairment resulting in failure to follow exposure guidelines, such as crowd mingling, hand washing and other decontamination procedures. In addition, many individuals that require various levels of intensive care may come in close contact with others with similar poor health conditions that may be carrying the virus. Lastly, the debilitating effects of AD may inherently increase susceptibility to the severe complications of SARS-CoV-2 infection known to occur in older frail people. For these reasons, it is critical to investigate the mitigating factors associated with increasing resilience to pathological consequences of infection to prevent increased morbidity and mortality in an already susceptible elderly population. Given that a major risk factor for developing severe and fatal SARS-CoV-2 pathology is aging, it is thus a centerpiece for the geroscience concept that examines the relationship between biological aging and age-related diseases through multiple processes, and that aging intervention requires targeting multiple aging processes. Our parent grant is set up to address this concept for AD. The development of a multidrug cocktail that targets multiple aging processes and increases resilience to AD pathology should, by definition, also increase resilience to SARS-CoV-2 pathology in AD patients. The hypothesis of this supplement proposal is that a drug cocktail of rapamycin, acarbose, and phenylbutyrate, targeting multiple aging processes, will increase resilience to the pathological consequences of SARS-CoV-2 infection in an aging mouse model of AD. Aim 1 will investigate effects of treatment with an anti-aging drug cocktail in AD mice infected with SARS-CoV-2. Aim 2 will develop pathology profiles to show that treatment of AD mice with an anti-aging drug cocktail will enhance resilience and improve health by targeting processes of aging and prevent the devastating pathology caused by SARS-CoV-2 infection. This approach has tremendous clinical health implications for AD patients but perhaps just as important for individuals in the early stage of disease such as mild cognitive impairment. The concept of a drug cocktail that could successfully increase resilience to COVID-19 pathology in Alzheimers disease patients would be expected to have a significant impact on the health of people at increased risk for infection.

摘要 此补充申请的家长补助金是R 01 AG 067193，“老年科学方法治疗 老年痴呆症”。补充提案是父母补助金的延伸，名为“老年科学” 研究阿尔茨海默病小鼠对SARS-CoV-2病理学恢复能力的方法”。的 扩展旨在研究存在认知障碍的COVID-19并发症， 老年小鼠模型中阿尔茨海默病的神经病理学病变。这与翻译相关 因为患有与阿尔茨海默病（AD）相关的认知障碍的患者， SARS-CoV-2感染的并发症涉及几个因素，包括认知障碍， 未遵守接触指南，如人群混合、洗手和其他去污 程序.此外，许多需要不同级别重症监护的人可能会接近 与可能携带病毒的健康状况类似的其他人接触。最后，使人衰弱的 AD的作用可能固有地增加对SARS-CoV-2感染的严重并发症的易感性 发生在年老体弱的人身上出于这些原因，调查减轻因素至关重要 与提高对感染病理后果的复原力以防止发病率增加有关 以及已经易感的老年人群的死亡率。考虑到发展严重的一个主要风险因素 而致命的SARS-CoV-2病理是衰老，因此它是老年科学概念的核心， 生物衰老与年龄相关疾病之间的关系是多过程的， 干预需要针对多个老化过程。我们的父母补助金是为了解决这个概念而设立的， AD.开发一种多药物鸡尾酒，针对多种衰老过程，并增加对衰老的适应能力。 根据定义，AD病理学也应该增加AD患者对SARS-CoV-2病理学的恢复力。的 该补充建议的假设是，雷帕霉素、阿卡波糖和 苯丁酸，针对多个老化过程，将增加对病理性衰老的恢复力。 SARS-CoV-2感染在老年AD小鼠模型中的后果。目标1将研究 用抗衰老药物鸡尾酒治疗感染SARS-CoV-2的AD小鼠。目标2将发展病理学 研究表明，用抗衰老药物鸡尾酒治疗AD小鼠将增强恢复力， 通过针对衰老过程和预防SARS-CoV-2引起的破坏性病理学， 感染这种方法对AD患者具有巨大的临床健康意义， 这对处于疾病早期阶段的个体如轻度认知障碍很重要。药物的概念 鸡尾酒可以成功地提高阿尔茨海默病患者对COVID-19病理学的适应力 预计将对感染风险增加的人的健康产生重大影响。