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

项目摘要 与肥胖和衰老强烈相关的常见病理状态是胰岛素抵抗（IR），其中 细胞变得对胰岛素的作用有抵抗力。IR是糖尿病前期的标志，影响三分之一的美国人。它 也是2型糖尿病、身体机能障碍、心脏病和痴呆症的主要危险因素。 除了运动和饮食，存在有限的基于机制的策略来改善IR。 肥胖和衰老的主要原因是p21 Cip 1高表达细胞（p21 high）在各种组织中的积累。但 p21 high细胞在IR和身体功能障碍中的作用仍然很大程度上未知。来研究 p21 high细胞和IR，我们已经建立并验证了一种新的“p21-Cre”转基因小鼠模型， p21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。这种新颖的模式 使我们能够在体内监测、杀死或调节p21 high细胞而不影响其他细胞。在我们的初步研究中， 我们发现肥胖小鼠中p21 high细胞的间歇性清除显著加重IR，表明 靶向这些细胞的策略可能会导致新的方法来管理IR和代谢功能障碍。 基于这些发现，我们将测试我们的中心假设，即靶向p21 high细胞将减轻代谢 以及与肥胖相关的身体机能障碍。我们将使用p21-Cre小鼠模型来检查作用（Aim 1)以及p21 high细胞在IR和躯体功能障碍中的潜在机制（目的2）。我们还将利用 强大的单细胞转录组学（SCT）技术，以揭示异质性和保守的转录组学 这些p21 high细胞在肥胖组织中的特征。该项目将对老龄化和 通过确定p21 high细胞如何促进IR来研究肥胖。使用多种体内模型， 单细胞转录组学的强大方法，我们期望获得对p21 high的全面了解 细胞（在功能和表达水平）。这项工作的结果也将使未来的测试， 药物干预，消除这些细胞，不仅治疗代谢功能障碍，而且还广泛的 与年龄有关的疾病。

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.