β cell dysfunction during aging: Studies on the role of p21 in the regulation of the Unfolded Protein Response

损害组织和器官功能的某些细胞群体的进行性丧失代表着 糖尿病等与年龄相关的疾病的一个共同特征。内质网(ER)应激一直是 与糖尿病中β细胞的进行性细胞丢失有关，这种细胞丢失发生在衰老过程中。ER应激是诱发的 当各种内在或外在因素导致错误折叠和未折叠的蛋白质在内质网中积累时 产生不利于细胞生存和功能的条件。内质网应激的分辨率为 通过启动一种称为未折叠蛋白的生存适应性生物化学级联来实现的 反应(UPR)，旨在恢复组织动态平衡。然而，当内质网应激持续或严重时， 与UPR相关的促凋亡信号主要清除受损细胞并损害 在衰老过程中占主导地位的组织和器官功能。尤其是在2型糖尿病中，UPR逐渐 导致β细胞凋亡，最终导致胰腺功能障碍，导致AGE- 相关的糖尿病。 可以想象，用于普遍定期审议的调制器的标识，特别是那些能够重新识别的调制器， 加强其促进生存的作用，而不是其促凋亡的活性，可能对衰老特别有益。 关联条件。我们的实验室发现，细胞周期调节因子p21就是这样一种调节器。 这能够抑制UPR的促凋亡活性。在本研究中，我们建议评估 内质网应激的诱导，以及p21在衰老中的调节作用。通过使用分离的胰岛 我们将以小鼠和老年小鼠为模型，评估UPR是如何与年龄相关的，以及它是如何影响的 胰岛的功能和生存。在我们的研究中，来自野生型、p21缺失、p53缺失和CHOP-1的胰岛 将使用有缺陷的小鼠。我们的具体目标是：1.监测p21表达和UPR的变化 不同年龄胰岛对内质网应激的诱导作用。2.探索药理学和遗传性 P21表达调控对胰岛存活和功能的影响与年龄相关 在内质网应激期间。雄鼠和雌鼠都将包括在我们的分析中，因为性别差异 可能与不同的普遍定期审议相关反应有关。可以想象，我们的发现将对这次行动起到启发作用。 P21、内质网应激和衰老之间具有生物学意义和临床相关性的联系，并可能发现 在年龄相关性糖尿病治疗中的应用。

The progressive loss of certain cell populations that compromises tissue and organ function represents a common feature of age-associated diseases such as diabetes. Endoplasmic reticulum (ER) stress has been associated to this progressive cell loss of β cells in diabetes that occurs during aging. ER stress is induced when various intrinsic or extrinsic factors cause the accumulation of misfolded and unfolded proteins in the ER generating conditions that are unfavorable for the cells’ survival and function. Resolution of ER stress is attained by the initiation of a prosurvival adaptive biochemical cascade, designated as the unfolded protein response (UPR), which aims to restore tissue homeostasis. When however ER stress is prolonged or severe, pro-apoptotic signals associated with the UPR predominate eliminating the damaged cells and compromising tissue and organ function which prevails during aging. In type 2 diabetes in particular, UPR progressively causes beta cell apoptosis and ultimately, pancreatic dysfunction contributing to the pathogenesis of age- associated diabetes. It is conceivable that the identification of modulators for the UPR, and particularly those capable of re- enforcing its pro-survival as opposed to its pro-apoptotic activity, may be of particular benefit in aging- associated conditions. Our laboratory discovered that the cell cycle regulator p21 represents such a modulator that is capable of inhibiting the pro-apoptotic activity of the UPR. In the present study we propose to evaluate the induction of ER stress, and the regulatory role of p21 in relation to aging. By using pancreatic islets isolated from young and old mice as a model we will assess how UPR is induced in relation to age and how it affects islets’ function and survival. For our studies islets from wild type, p21-deficient, p53-deficient and CHOP- deficient mice will be used. Our specific aims are: 1. To monitor the profile of p21 expression and UPR induction in islets in response to ER stress at different ages. 2. To explore if pharmacological and genetic modulation of p21 expression affects the survival and function of pancreatic islets in association with age during ER stress. Both male and female mice will be included in our analyses since gender-specific differences may be linked to distinct UPR-related responses. It is conceivable that our findings will illuminate the operation of a biologically important and clinically relevant link between p21, ER stress and aging and may find application in the management of age-associated diabetes.