Senolysis in kidney disease: Therapeutic potential and risks

肾脏疾病中的衰老：治疗潜力和风险

• 批准号: 440774218
• 负责人: Professorin Dr. Anette Melk, Ph.D.
• 金额: --
• 依托单位: Klinik für pädiatrische Nieren-, Leber- und Stoffwechselerkrankungen
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/440774218?language=en
• 关键词: Senolysis; kidney; disease; Therapeutic; potential

The importance of cellular senescence, a cell fate program, for aging, but also several disease processes has been shown over the past decade. Senescent cells are locked in a non-dividing state, in which they are no longer able to maintain tissue integrity and are harmful for normal organ maintenance by creation of a pro-inflammatory microenvironment. In fact, novel strategies in targeting senescent cells have shown promise in several organ systems to counteract functional decline, chronic inflammation and age-dependent loss of repair capacity. Senescent cells accumulate in the kidney with advancing age and also occur independent of age as a part of renal diseases making them an important target for therapeutic approaches.Our objective is to evaluate known senolytic drugs for their efficacy and safety in our established cellular and animal models. We will test the hypothesis that selective killing of senescent cells can be utilized to improve age-associated loss of kidney function and to counteract the accelerated aging phenotype. For this purpose we will evaluate in Aim 1 the most effective way to decrease the burden of senescent cells in the kidney. Based on in vitro selection of the most promising senolytic compounds, we will then further evaluate whether short-term application of those drugs will improve outcome after acute kidney injury in chronologically aged mice as well as in young mice, which have undergone pro-senescent kidney stress. In addition, we will initiate long-term drug application to study its effect on chronological aging changes in the kidney. Aim 2 addresses the question whether peri-operative application of such senolytic compounds leads to an improvement in transplantation outcome when marginal donor kidneys are utilized. For this approach, we will first test different senolytic drugs ex vivo for their potential to eliminate senescent cells under perfusion conditions and will then further evaluate the outcome of pre-treated organs in isogeneic and allogeneic settings. In a translational approach, we are going to use explanted kidneys to see whether our findings can be translated into the human setting.The overall goal of this study is twofold: firstly, to evaluate ‘senolysis’ as a novel approach for improving the outcome of diseased native kidneys and of renal transplants; and secondly, to provide evidence for the causal relationship between the presence of senescent cells and renal functional decline.

细胞衰老（一种细胞命运程序）对于衰老以及多种疾病过程的重要性在过去十年中已得到证明。衰老细胞被锁定在非分裂状态，在这种状态下它们不再能够维持组织完整性，并且通过产生促炎微环境而对正常器官的维护有害。事实上，针对衰老细胞的新策略已在多个器官系统中显示出有望抵消功能衰退、慢性炎症和年龄依赖性修复能力丧失的希望。衰老细胞随着年龄的增长在肾脏中积累，并且作为肾脏疾病的一部分，其发生与年龄无关，这使得它们成为治疗方法的重要目标。我们的目标是在我们建立的细胞和动物模型中评估已知的衰老药物的功效和安全性。我们将检验这样的假设：选择性杀死衰老细胞可用于改善与年龄相关的肾功能丧失并抵消加速衰老的表型。为此，我们将在目标 1 中评估减轻肾脏衰老细胞负担的最有效方法。基于对最有前途的衰老化合物的体外选择，我们将进一步评估短期应用这些药物是否会改善老化小鼠以及经历了促衰老肾脏应激的年轻小鼠急性肾损伤后的结果。此外，我们将启动长期药物应用，研究其对肾脏随时间老化变化的影响。目标 2 解决了当使用边缘供体肾脏时，围手术期应用此类抗衰老化合物是否会改善移植结果的问题。对于这种方法，我们将首先在体外测试不同的衰老药物在灌注条件下消除衰老细胞的潜力，然后进一步评估在同基因和同种异体环境中预处理器官的结果。在转化方法中，我们将使用外植肾脏来看看我们的发现是否可以转化为人类环境。这项研究的总体目标有两个：首先，评估“衰老作用”作为改善患病天然肾脏和肾移植结果的新方法；其次，为衰老细胞的存在与肾功能衰退之间的因果关系提供证据。