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: 10394412
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394412
• 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; translational potential

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 阿尔茨海默病（Alzheimer's disease，AD）是最常见的年龄依赖性神经退行性疾病。当前没有任何 改善疾病的治疗是临床上有效治疗AD的方法。需要新的治疗靶点， AD的治疗和预防。延缓基本的衰老过程可能同时缓解 与年龄有关的疾病，包括AD。衰老细胞在各种组织中的积累是衰老的原因之一。 衰老的最显著特征。清除衰老细胞可以减缓生物衰老过程， 各种临床相关的后果。然而，衰老细胞在衰老中的作用和潜在机制尚不清楚。 AD还没有完全理解。为了研究衰老细胞和AD之间的关系，我们产生了 并验证了一种新的“p21-Cre”转基因小鼠模型，该模型含有p21（细胞增殖的关键标志物）， 衰老）启动子驱动与他莫昔芬诱导型雌激素受体（ER）元件融合的Cre。这本小说 该模型使我们能够在体内监测、杀死或调节p21高表达（p21 high）细胞， 其他细胞。在我们的初步研究中，我们发现p21 high细胞在AD脑中积聚。在这项研究中，我们将 测试我们的中心假设，靶向p21 high细胞将减轻AD和认知功能障碍。我们将使用 p21-Cre小鼠模型以检查p21 high细胞在AD中的作用。该项目将对双方产生广泛影响。 通过确定p21 high细胞如何促进AD来研究衰老和AD。使用多种体内模型，我们 以期对p21 high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 使未来的药物干预试验，消除这些细胞，不仅治疗AD，但也 与年龄有关的各种疾病。

项目成果

Senolytics improve bone forming potential of bone marrow mesenchymal stem cells from aged mice.

• DOI: 10.1038/s41536-021-00145-z
• 发表时间: 2021-06-11
• 期刊: NPJ Regenerative medicine
• 影响因子: 7.2
• 作者: Zhou Y;Xin X;Wang L;Wang B;Chen L;Liu O;Rowe DW;Xu M
• 通讯作者: Xu M

The heterogeneity of cellular senescence: insights at the single-cell level.

• DOI: 10.1016/j.tcb.2022.04.011
• 发表时间: 2023-01
• 期刊: TRENDS IN CELL BIOLOGY
• 影响因子: 19
• 作者: Cohn, Rachel L.;Gasek, Nathan S.;Kuchel, George A.;Xu, Ming
• 通讯作者: Xu, Ming

Senescence-induced changes in CD4 T cell differentiation can be alleviated by treatment with senolytics.

衰老引起的CD4 T细胞分化变化可以通过用鼻溶液治疗来缓解。

• DOI: 10.1111/acel.13525
• 发表时间: 2022-01
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Lorenzo EC;Torrance BL;Keilich SR;Al-Naggar I;Harrison A;Xu M;Bartley JM;Haynes L
• 通讯作者: Haynes L