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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.

项目总结