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The impact of primary and secondary epithelial senescence on renal function and fibrosis

原发性和继发性上皮衰老对肾功能和纤维化的影响

基本信息

批准号：
MR/T008253/1
负责人：
金额：
$ 40.71万
依托单位：
University of Edinburgh
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT008253%2F1
关键词：
impact primary secondary epithelial senescence

项目摘要

Chronic Kidney Disease (CKD) affects over 850 million people worldwide. It is a disease process which causes the kidneys to become scarred; a term we call 'fibrosis'. Injuries can range from simple things; like short periods of infection and low blood pressure to more complicated and rarer diseases which affect the kidney tissue itself. Regardless of the initial injury and regardless of this initial injury going away completely, we believe that the kidney is often permanently damaged. Often we don't measure this in blood or urine tests; these become normal again. But we know from observational data that having one such episode, even if brief and completely resolved, puts a person at significantly higher risk of developing progressive CKD. At present, we don't have any treatments to stop or slow this progression and this can ultimately lead to complete kidney failure and the requirement for regular dialysis or kidney transplantation. We also know that in individuals with CKD, although the scarring is in the kidneys, their chance of heart disease, and death from heart disease is significantly increased.There are certain processes and cellular changes which occur in response to these injuries (not just in a kidney, but in other organs too) which we believe contribute to this progressive scarring. If they can be targeted and blocked it could prevent this inevitable scar formation. This PhD will focus on one such pathway, and a group of cells; called 'senescent cells'. These are cells which are damaged but do not die in a normal programmed way. We know that these cells can persist and communicate with other cells in the body to promote scarring. We find senescent cells in human kidneys in lots of different kidney diseases, we find more in older kidneys and more in the aftermath of kidney injury. So far; we know that we can treat and remove these cells safely in mice and that the mice live longer and healthier lives. If we can study these cells and their signalling pathways in greater detail we believe this would be a potentially very successful treatment and would impact significantly on human kidney disease. My supervisor's group's recent work has shown that more than one kind of senescent cell exists in the kidney. Some of these cells ('primary senescent cells') occur in direct response to kidney injury. Others ('secondary senescent cells') are generated later in response to signals coming from the primary senescent cells. Important experimental work in the liver has shown that by blocking the signals from the primary senescent cells - it is possible to prevent secondary senescence from happening, and this helps the liver to regenerate after injuries without scarring. It seems likely that similar pathways will contribute to kidney scarring - but this has yet to be tested.In my fellowship, I will use a novel type of mouse where I can generate senescent cells in one particular cell type ('epithelial cells') in the kidney using a drug treatment with no associated kidney injury. This will allow me to understand how primary senescent cells lead to both secondary senescence and scarring by studying mice and kidney cells growing in the laboratory. By understanding these processes, I hope to discover how they can be blocked in the laboratory, in mice, and eventually in studies in patients - leading to novel treatments to prevent progressive fibrosis in the kidney and other organs.

慢性肾脏病（CKD）影响全球超过8.5亿人。这是一种导致肾脏出现疤痕的疾病过程;我们称之为“纤维化”。损伤的范围可以从简单的事情;像短期感染和低血压到影响肾脏组织本身的更复杂和更罕见的疾病。不管最初的损伤如何，也不管最初的损伤是否完全消失，我们认为肾脏通常会受到永久性损伤。我们通常不会在血液或尿液测试中测量这一点;这些又恢复正常。但我们从观察数据中知道，有一次这样的发作，即使短暂和完全解决，也会使一个人发生进展性CKD的风险显著增加。目前，我们没有任何治疗方法来阻止或减缓这种进展，这最终可能导致完全肾衰竭，需要定期透析或肾移植。我们还知道，在CKD患者中，虽然瘢痕形成在肾脏，但他们患心脏病的几率和死于心脏病的几率显著增加。我们认为，这些损伤（不仅在肾脏，而且在其他器官）会导致某些过程和细胞变化，从而导致这种进行性瘢痕形成。如果它们可以被靶向和阻断，它可以防止这种不可避免的疤痕形成。这个博士将专注于一个这样的途径，和一组细胞;称为“衰老细胞”。这些细胞受损，但不会以正常的编程方式死亡。我们知道，这些细胞可以持续存在，并与体内其他细胞交流，以促进疤痕形成。我们在许多不同的肾脏疾病中发现了人类肾脏中的衰老细胞，我们在老年肾脏中发现更多，在肾损伤后发现更多。到目前为止，我们知道我们可以在小鼠中安全地处理和去除这些细胞，并且小鼠活得更长，更健康。如果我们能够更详细地研究这些细胞及其信号通路，我们相信这将是一种潜在的非常成功的治疗方法，并将对人类肾脏疾病产生重大影响。我的导师小组最近的工作表明，肾脏中存在不止一种衰老细胞。这些细胞中的一些（“初级衰老细胞”）直接响应于肾损伤而发生。其他的（“次级衰老细胞”）是在随后响应来自初级衰老细胞的信号而产生的。在肝脏中的重要实验工作表明，通过阻断来自初级衰老细胞的信号，可以防止继发性衰老的发生，这有助于肝脏在受伤后再生而不会留下疤痕。在我的研究中，我将使用一种新型的小鼠，在这种小鼠中，我可以通过药物治疗在肾脏中的一种特定细胞类型（“上皮细胞”）中产生衰老细胞，而不会造成相关的肾损伤。这将使我能够通过研究实验室中生长的小鼠和肾细胞来了解初级衰老细胞如何导致继发性衰老和瘢痕形成。通过了解这些过程，我希望发现它们如何在实验室，小鼠中以及最终在患者研究中被阻断-从而导致新的治疗方法来预防肾脏和其他器官的进行性纤维化。