Decoding senescent cell signalling pathways in tissue fibrosis

解码组织纤维化中的衰老细胞信号通路

• 批准号: MR/X006735/1
• 负责人: David Ferenbach
• 金额: $ 254.52万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX006735%2F1
• 关键词: Decoding; senescent; cell; signalling; pathways

Chronic kidney disease (CKD) affects over 700 million people worldwide and is more common in older patients and survivors of previous acute kidney injury. Treatment options are limited, and CKD often progresses despite maximal current medical therapy. There is an unmet need for novel treatments to halt the progressive scarring typical of CKD.My previous work has shown that senescent cells ("SCs" - altered, permanently growth-arrested cells) are present in increased numbers in human CKD, and that in animal models of kidney injury and ageing, the presence of SCs promotes progressive scarring and functional loss. Our studies also showed that treatments that kill senescent cells improve the ability of older and previously damaged kidneys to regenerate after further injuries. I hypothesise that inhibiting signalling pathways in chronic senescent cells (SCs) will provide a more precise way to preserve renal structure and function by preventing their effects on scarring and promoting their clearance. To do this, we will first examine samples of human kidneys with CKD - and use new, high-resolution techniques to explore SC behaviour at single cell resolution - identifying which pathways connect SCs to the production of fibrosis, inflammation and worse long term outcomes.Next, we will dissect out the influence of SC derived pathways on inflammatory cells and on scar producing cells using an advanced 'organ-on-a-chip' cell culture environment which will allow us to tease out exactly which pathways account for the ability of SCs to resist clearance by immune cells, and how SCs directly or indirectly cause fibrosis to be produced in a way not possible in a whole kidney. In collaboration with our colleagues in the Edinburgh Drug Discovery Unit we will then use their expertise to perform highly efficient, automated testing of thousands of potential drug compounds - looking for agents which inhibit the pathways we have identified as causative in our earlier work - and which selectively promote inactivation and/or clearance of SCs without side effects on healthy cells.We will next test the safety and efficacy of treatments designed to prevent SC driven kidney scarring, whilst promoting the healthy clearance of SCs in mouse models of kidney fibrosis. We will use a strain of mouse where SCs can be labelled with two different fluorescent colours, giving us additional information on whether SCs behave differently the longer they persist after initial injury. We will be able to examine the effects of our drugs on SC number and behaviour, as well as immune cell and fibroblast (the type of cell responsible for the production of scarring within the kidney) behaviour, measuring how well each drug protects the function of the kidney after injury. Finally, we will move our work from bench back to human kidneys - which have been offered for transplantation but deemed unsuitable for re-implantation. Using machinery to keep the kidneys alive, warm and oxygenated we will administer and observe the safety and efficacy of our best-performing targeted anti-SC therapy in the human kidney, setting the stage for early translation to clinical studies.

慢性肾脏疾病（CKD）影响全球超过7亿人，在老年患者和先前急性肾脏损伤的幸存者中更为常见。治疗方案有限，尽管当前的医疗疗法最大，CKD经常进展。尚未满足新的治疗方法来停止CKD的典型进行性疤痕。肾脏损伤和衰老的动物模型，SC的存在促进了进行性疤痕和功能损失。我们的研究还表明，杀死衰老细胞的治疗方法可以提高较老和以前损坏的肾脏在进一步受伤后再生的能力。我假设抑制慢性衰老细胞（SC）中的信号传导途径将通过防止其对疤痕和促进其清除率的影响来提供更精确的方法来保持肾脏结构和功能。为此，我们将首先检查使用CKD的人类肾脏样品 - 并使用新的高分辨率技术在单细胞分辨率下探索SC行为 - 确定哪种途径将SC与纤维化，炎症和较差的长期结构相关联。接下来，我们将使用先进的“芯片上的”细胞培养环境来剖定SC衍生途径对炎症细胞和疤痕产生细胞的影响，这将使我们能够准确取消哪个途径来解释哪个途径的能力。 SC可抵抗免疫细胞清除，以及在整个肾脏中无法直接或间接导致产生纤维化的SC。通过与爱丁堡药物发现单位的同事合作，我们将使用他们的专业知识对数千种潜在的药物化合物进行高效，自动测试 - 寻找抑制我们在早期工作中确定为病因的药物 - 以及哪些途径 - 以及有选择地促进对健康细胞没有副作用的SC的失活和/或清除率。我们接下来将测试旨在防止SC驱动的肾脏疤痕的治疗的安全性和功效，同时促进肾纤维化小鼠模型中SC的健康清除率。我们将使用一种小鼠菌株，其中SC可以用两种不同的荧光颜色标记，从而为我们提供了有关SC在初次受伤后持续时间持续时间是否持续时间的其他信息。我们将能够检查药物对SC数量和行为的影响，以及免疫细胞和成纤维细胞（负责肾脏内疤痕产生的细胞类型）行为，以衡量每种药物如何保护每个药物的功能受伤后的肾脏。最后，我们将把工作从板凳转移到人类肾脏 - 已提供用于移植的肾脏，但认为不适合重新植入。使用机械使肾脏保持活力，温暖和氧化，我们将管理和观察人类肾脏中最出色的靶向抗SC治疗的安全性和功效，为早期转化为临床研究奠定了基础。