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.

慢性肾脏病（CKD）影响全球超过7亿人，在老年患者和既往急性肾损伤的幸存者中更常见。治疗选择有限，尽管目前最大的药物治疗，CKD仍经常进展。对于阻止CKD典型的进行性瘢痕形成的新型治疗方法存在未满足的需求。我以前的工作已经表明，衰老细胞（“SC”改变的、永久生长停滞的细胞）在人类CKD中以增加的数量存在，并且在肾损伤和衰老的动物模型中，SC的存在促进进行性瘢痕形成和功能丧失。我们的研究还表明，杀死衰老细胞的治疗方法可以提高老年和先前受损的肾脏在进一步损伤后再生的能力。我假设，抑制慢性衰老细胞（SC）中的信号通路将提供一种更精确的方法，通过防止其对瘢痕形成的影响并促进其清除来保护肾脏结构和功能。为此，我们将首先检查患有CKD的人类肾脏样本-并使用新的高分辨率技术以单细胞分辨率探索SC行为-确定哪些途径将SC与纤维化，炎症和更糟糕的长期结果的产生联系起来。接下来，我们将使用一种先进的“器官上的细胞”来剖析SC衍生途径对炎症细胞和瘢痕产生细胞的影响，这将使我们能够准确地梳理出哪些途径解释了干细胞抵抗免疫细胞清除的能力，以及干细胞如何直接或间接地导致纤维化以一种在整个肾脏中不可能的方式产生。与爱丁堡药物发现部门的同事合作，我们将利用他们的专业知识，自动测试数千种潜在的药物化合物-寻找抑制我们在早期工作中确定为致病途径的药物-以及选择性促进灭活和/或灭活的药物。我们接下来将测试设计用于预防SC驱动的肾瘢痕形成的治疗的安全性和有效性，同时促进肾纤维化小鼠模型中SC的健康清除。我们将使用一种小鼠品系，其中SC可以用两种不同的荧光颜色标记，为我们提供更多信息，说明SC在初始损伤后持续时间越长，其行为是否会有所不同。我们将能够检查我们的药物对SC数量和行为的影响，以及免疫细胞和成纤维细胞（负责在肾脏内产生瘢痕的细胞类型）行为，测量每种药物在损伤后保护肾脏功能的效果。最后，我们将把我们的工作从实验室移回到人类肾脏上--这是一种已经被提供用于移植但被认为不适合重新植入的肾脏。使用机械来保持肾脏存活，温暖和充氧，我们将管理和观察我们在人类肾脏中表现最好的靶向抗SC治疗的安全性和有效性，为早期转化为临床研究奠定基础。