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

项目总结 与肥胖和衰老密切相关的一种常见病理状态是胰岛素抵抗(IR) 细胞对胰岛素的作用产生抵抗力。IR是糖尿病前期的一个标志，影响着三分之一的美国人。它 也是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。 除了锻炼和饮食之外，改善胰岛素抵抗的机制策略也很有限。另一个共享功能 肥胖和衰老的主要原因是p21Cip1高表达细胞在各种组织中的聚集。然而， P21High细胞在IR和生理功能障碍中的作用尚不清楚。要考察两国之间的关系 P21High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，该模型包含一个 P21启动子驱动Cre与他莫昔芬诱导的雌激素受体(ER)元件融合。这种新颖的模式 使我们能够在不影响其他细胞的情况下监测、杀死或调节体内的p21High细胞。在我们的初步研究中， 我们发现，肥胖小鼠间歇性清除p21High细胞显著缓解IR，这表明 针对这些细胞的策略可能导致治疗IR和代谢功能障碍的新方法。 基于这些发现，我们将验证我们的中心假设，即靶向p21高表达细胞将缓解代谢 以及与肥胖相关的身体功能障碍。我们将使用p21-CRE小鼠模型来检查角色(Aim 1)和p21高表达细胞在IR和生理功能障碍中的作用机制(目的2)。我们还将利用 强大的单细胞转录组学(SCT)技术，揭示异质性和保守的转录组学 肥胖组织中这些p21高表达细胞的特征。该项目将对老龄化和 通过确定p21High细胞如何对IR做出贡献来研究肥胖。使用多个体内模型，再加上 单细胞转录的强大手段，我们期待着对p21High有一个全面的了解 体内的细胞(包括功能和表达水平)。这项工作的结果还将使未来的测试 消除这些细胞的药物干预不仅可以治疗代谢功能障碍，还可以治疗广泛的 一系列与年龄有关的疾病。

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.