Targeting p21-positive Senescent Cells in vivo for Alleviating Metabolic and Physical Dysfunction

靶向体内 p21 阳性衰老细胞以减轻代谢和身体功能障碍

基本信息

批准号：
10383716
负责人：
Ming Xu
金额：
$ 44.89万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10383716
关键词：
Affect Aging American Animal Model Automobile Driving Biological Aging Body Weight decreased CDKN2A gene Cell Aging Cells Chronic Disease Complement Coupled Data Dementia Disease Elements Enterobacteria phage P1 Cre recombinase Estrogen Receptors Exercise Foundations Functional disorder Future Genes Goals Heart Diseases Heterogeneity Insulin Insulin Resistance Intervention Kinetics Longevity Metabolic Metabolic dysfunction Modeling Monitor Natural History Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Outcome Pathologic Pathology Pathway interactions Pharmacology Physical Function Physical Performance Play Population Population Heterogeneity Prediabetes syndrome Research Resistance Resistance development Resources Risk Risk Factors Role Stress Stroke Tamoxifen Technology Testing Therapeutic Tissues Transgenic Mice Work age related base clinically relevant diet and exercise disability drug development experience frailty healthspan improved in vivo in vivo Model innovation insight loss of function mouse Cre recombinase mouse model novel novel strategies prevent promoter recombinase sarcopenia screening senescence transcriptomics translational potential

项目摘要

PROJECT SUMMARY A common pathological state strongly associated with both obesity and aging is insulin resistance (IR) in which cells become resistant to the effects of insulin. IR is a hallmark of prediabetes, affecting a third of Americans. It also represents a major risk factor for type 2 diabetes mellitus, physical dysfunction, heart disease, and dementia. Other than exercise and diet, limited mechanism-based strategies exist to improve IR. Another shared feature of obesity and aging is accumulation of p21Cip1–highly-expressing (p21high) cells in various tissues. However, the roles of p21high cells in IR and physical dysfunction remain largely unknown. To examine the relationship between p21high cells and IR, we have generated and validated a novel “p21-Cre” transgenic mouse model containing a p21 promoter driving a Cre fused to a tamoxifen-inducible estrogen receptor (ER) element. This novel model enables us to monitor, kill or modulate p21high cells in vivo without affecting other cells. In our preliminary studies, we find that intermittent clearance of p21high cells in obese mice significantly alleviates IR, indicating that strategies targeting these cells could result in novel approaches for managing IR and metabolic dysfunction. Based on these findings, we will test our central hypothesis that targeting p21high cells will alleviate metabolic and physical dysfunction associated with obesity. We will use p21-Cre mouse models to examine the role (Aim 1) and underlying mechanism (Aim 2) of p21high cells in IR and physical dysfunction. We will also leverage powerful single cell transcriptomics (SCT) technology to reveal the heterogeneity and conserved transcriptomic features of these p21high cells in tissues with obesity. This project will have a broad impact on both aging and obesity research by determining how p21high cells contribute to IR. Using multiple in vivo models, coupled with the powerful approach of single cell transcriptomics, we expect to gain a comprehensive understanding of p21high cells (at both functional and expression levels) in vivo. Results from this work will also enable future testing of pharmacological interventions that eliminate these cells to treat not only metabolic dysfunction, but also a wide range of age-related diseases.

项目摘要与肥胖和衰老密切相关的一个常见病理状态是胰岛素抵抗（IR），其中细胞对胰岛素的作用具有抗性。 IR是前糖尿病的标志，影响了三分之一的美国人。它还代表了2型糖尿病，身体功能障碍，心脏病和痴呆症的主要危险因素。除运动和饮食外，还存在有限的基于机制的策略以改善IR。另一个共享功能肥胖和衰老是各种组织中p21CIP1高表达（p21High）细胞的积累。但是， P21高细胞在IR和物理功能障碍中的作用在很大程度上未知。检查 P21高细胞和IR，我们已经生成并验证了一种新型的“ P21-CRE”转基因小鼠模型，其中包含A p21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。这个新颖的模型使我们能够在体内监测，杀死或调节p21高细胞，而不会影响其他细胞。在我们的初步研究中我们发现，肥胖小鼠中P21高细胞的间歇性清除显着减轻了IR，表明针对这些细胞的策略可能会导致用于管理IR和代谢功能障碍的新方法。基于这些发现，我们将测试我们的中心假设，即靶向P21高细胞将减轻代谢和与肥胖相关的身体功能障碍。我们将使用p21-cre鼠标模型来检查角色（目标 1）IR和物理功能障碍中P21高细胞的基本机制（AIM 2）。我们还将利用强大的单细胞转录组学（SCT）技术，以揭示异质性和构成转录组这些p21高细胞在肥胖的组织中的特征。该项目将对衰老和肥胖研究通过确定p21高细胞如何贡献IR。使用多个体内模型，与单细胞转录组学的强大方法，我们希望对P21高的全面了解细胞（在功能和表达水平上）在体内。这项工作的结果还将实现以后的测试消除这些细胞的药理干预措施不仅治疗代谢功能障碍，还可以治疗与年龄有关的疾病范围。