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

项目摘要 阿尔茨海默病(AD)是最常见的年龄依赖性神经退行性疾病。目前，没有 临床上运用调理疗法可有效治疗阿尔茨海默病。需要新的治疗靶点 AD的治疗和预防。推迟基本的老化过程可能会同时缓解一系列 与年龄有关的疾病，包括阿尔茨海默病。衰老细胞在各种组织中的积累是 最显著的老龄化特征。清除衰老细胞可以减缓生物衰老过程，并 各种与临床相关的后果。然而，衰老细胞在糖尿病中的作用和潜在机制 人们对广告的理解还不完全。为了研究衰老细胞和阿尔茨海默病之间的关系，我们生成了 并验证了一种新的含有p21(细胞的关键标志)的p21-Cre转基因小鼠模型 衰老)启动子驱动Cre融合到他莫昔芬诱导的雌激素受体(ER)元件。这部小说 模型使我们能够在体内监测、杀死或调节p21高表达的细胞，而不影响 其他细胞。在我们的初步研究中，我们发现p21High细胞在AD大脑中积聚。在这项研究中，我们将 测试我们的中心假设，即靶向p21High细胞将缓解AD和认知功能障碍。我们将使用 建立p21-Cre小鼠模型，检测p21High细胞在AD中的作用。这个项目将对双方产生广泛的影响 通过确定p21High细胞在AD中的作用来研究衰老和AD。使用多个活体模型，我们 期望在体内对p21High细胞在AD中的作用有一个全面的了解。这项工作的结果也将 使未来能够测试消除这些细胞的药物干预不仅可以治疗AD，而且还可以治疗 各种与年龄有关的疾病。

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.