Targeting P21-Highly-Expressing Senescent Cells In Vivo for Improving Cognitive Function in the Alzheimers Diseases

体内靶向高表达 P21 的衰老细胞可改善阿尔茨海默病的认知功能

• 批准号: 10196320
• 负责人: Ming Xu
• 金额: $ 16.4万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196320
• 关键词: APP-PS1; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloid deposition; Animal Model; Automobile Driving; Biological Aging; Brain; CDKN2A gene; Cell Aging; Cells; Clinic; Complement; Data; Disease; Elements; Enterobacteria phage P1 Cre recombinase; Estrogen Receptors; Foundations; Functional disorder; Future; Genes; Goals; Human Amyloid Precursor Protein; Impaired cognition; Intervention; Knowledge; Label; Lead; Modeling; Monitor; Mus; Nature; Neurodegenerative Disorders; Neurons; Outcome; Pathogenesis; Pathologic; Pathology; Pharmacology; Play; Population Heterogeneity; Prevention; Process; Research; Role; Senile Plaques; Stress; Synapses; Tamoxifen; Testing; Tissues; Transgenic Mice; Work; age related; amyloid pathology; base; cell type; clinically relevant; cognitive function; drug development; improved; in vivo; in vivo Model; mouse model; mutant; neuron loss; new therapeutic target; novel; presenilin-1; promoter; senescence; tau Proteins; tau aggregation

Project Summary Alzheimer's disease (AD) is the most common age-dependent neurodegenerative disease. Currently, no disease-modifying therapy is available to treat AD effectively in clinic. New therapeutic targets are desired for AD treatment and prevention. Delaying the fundamental aging process might simultaneously alleviate a range of age-related diseases, including AD. The accumulation of senescent cells in various tissues is one of the most prominent features of aging. Clearance of senescent cells can slow down biological aging process and various clinically-relevant consequences. However, the role and underlying mechanisms of senescent cells in AD is not fully understood. To examine the relationship between senescent cells and AD, we have generated and validated a novel “p21-Cre” transgenic mouse model containing a p21 (a key marker for cellular senescence) promoter driving a Cre fused to a tamoxifen-inducible estrogen receptor (ER) element. This novel model enables us to monitor, kill or modulate p21-highly-expressing (p21high) cells in vivo without affecting other cells. In our preliminary studies, we find that p21high cells accumulate in AD brains. In this study, we will test our central hypothesis that targeting p21high cells will alleviate AD and cognitive dysfunction. We will use p21-Cre mouse models to examine the role of p21high cells in AD. This project will have a broad impact on both aging and AD research by determining how p21high cells contribute to AD. Using multiple in vivo models, we expect to gain a comprehensive understanding of p21high cells in AD in vivo. Results from this work will also enable future testing of pharmacological interventions that eliminate these cells to treat not only AD, but also a wide range of age-related diseases.

项目摘要 阿尔茨海默氏病（AD）是最常见的年龄依赖性神经退行性疾病。目前，没有 可以在诊所中有效治疗疾病改良疗法。需要新的治疗靶标 广告处理和预防。延迟基本的衰老过程可能会简单地减轻范围 与年龄有关的疾病，包括AD。在不同时期，感官细胞的积累是 衰老最突出的特征。感觉细胞的清除可以减慢生物衰老过程，并 各种临床上的后果。但是，感觉细胞的作用和潜在机制 广告尚未完全理解。为了检查感觉细胞与AD之间的关系，我们已经产生了 并验证了一种新型的“ p21-cre”转基因小鼠模型，该模型包含P21（细胞的关键标记 启动子驱动融合到他莫昔芬诱导的雌激素受体（ER）元件的CRE。这本小说 模型使我们能够在体内监测，杀死或调节P21-High-high-high-typress（p21High）细胞而不会影响 其他细胞。在我们的初步研究中，我们发现p21高细胞在AD大脑中积聚。在这项研究中，我们将 检验我们的核心假设，即靶向P21高细胞将减轻AD和认知功能障碍。我们将使用 p21-cre小鼠模型检查了p21高细胞在AD中的作用。这个项目将对这两者产生广泛的影响 通过确定p21高细胞如何对AD贡献衰老和AD研究。使用多个体内模型，我们 期望对体内AD中的P21高细胞有全面的了解。这项工作的结果也将 实现对消除这些细胞的药物干预措施的未来测试，不仅可以治疗AD，还可以治疗AD 广泛的与年龄有关的疾病。