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

衰老过程中β细胞功能障碍：p21 在未折叠蛋白反应调节中的作用研究

• 批准号: 9178859
• 负责人: Hippokratis Kiaris
• 金额: $ 7.33万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9178859
• 关键词: Affect; Age; Age Factors; Aging; Apoptosis; Apoptotic; Beta Cell; Biochemical; CDKN1A gene; Caspase; Cell Cycle; Cell Survival; Cell physiology; Cells; Cessation of life; Data; Diabetes Mellitus; Disease; Elderly; Endoplasmic Reticulum; Female; Functional disorder; Funding; Gender; Genetic; Genotype; Glucose; Homeostasis; Insulin; Islets of Langerhans; Laboratories; Life; Link; Measurement; Modeling; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Pancreas; Pathogenesis; Pathology; Pilot Projects; Population; Prevalence; Proteins; Regulation; Reporting; Resolution; Role; Series; Signal Transduction; Structure of beta Cell of islet; TP53 gene; Testing; Tissues; Tunicamycin; Validation; age related; anti aging; base; biological adaptation to stress; cell injury; clinically relevant; endoplasmic reticulum stress; islet; male; mouse model; nervous system disorder; oncoprotein p21; operation; pancreatic islet function; protective effect; research study; response; transcription factor CHOP

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.

某些细胞群的逐渐丧失损害了组织和器官的功能， 这是与年龄相关的疾病如糖尿病的一个共同特征。内质网（ER）应激已被 与糖尿病中β细胞在衰老过程中发生的这种进行性细胞损失有关。电流变应力被诱导 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ER中积累时， 产生不利于细胞存活和功能的条件。ER应力的分辨率为 通过启动前生存适应性生化级联反应获得，称为未折叠蛋白 反应（UPR），旨在恢复组织稳态。然而，当内质网应激延长或严重时， 与UPR相关的促细胞凋亡信号占主导地位， 组织和器官的功能，在老化过程中占主导地位。特别是在2型糖尿病中， 导致β细胞凋亡，并最终导致胰腺功能障碍，从而导致衰老的发病机制- 相关糖尿病 可以想象的是，鉴定用于UPR的调节剂，特别是那些能够重新调节的调节剂， 加强其促存活活性而不是促凋亡活性，可能对衰老特别有益- 相关条件。我们的实验室发现，细胞周期调节因子p21代表了这样一种调节剂， 其能够抑制UPR的促凋亡活性。在本研究中，我们建议评估 ER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 从年轻和年老的小鼠作为模型，我们将评估UPR是如何诱导与年龄有关，以及它如何影响 胰岛的功能和存活。对于我们的研究，来自野生型、p21缺陷型、p53缺陷型和CHOP缺陷型的胰岛。 将使用缺陷型小鼠。我们的具体目标是：1.监测p21表达和UPR 在不同年龄响应于ER应激的胰岛中的诱导。2.探索药理学和遗传学 p21表达的调节影响与年龄相关的胰岛的存活和功能 在ER压力下。我们的分析将包括雄性和雌性小鼠，因为性别特异性差异 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有助于 p21、ER应激和衰老之间的生物学重要和临床相关联系，并可能发现 在年龄相关性糖尿病管理中的应用。