Reducing organ fibrosis by targeting a novel pro-fibrotic CLEC4D expressing myeloid subset.

通过靶向表达新型促纤维化 CLEC4D 的骨髓亚群来减少器官纤维化。

• 批准号: MR/Y014103/1
• 负责人: Laura Denby
• 金额: $ 86.35万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY014103%2F1
• 关键词: Reducing; organ; fibrosis; targeting; novel

Patients with kidney and liver disease lose their normal organ tissue as it is progressively replaced by scar tissue, resulting in a reduction in organ function. Eventually, this may lead to organ failure and the need for patients to undergo chronic dialysis therapy or kidney/liver transplantation. Despite these life-saving therapies, kidney and liver disease are the 11th and 12th leading causes of death. Unfortunately, the number of patients with kidney and liver disease is continuing to rise and treatment options remain limited, therefore it is vitally important that researchers identify novel therapies that slow progression of disease.Regardless of the underlying cause of the injury, damage to the kidneys and liver results in recruitment of white blood cells to the injured organs. These cells are part of the body's immune system that is important for fighting infection, however during organ injury they may promote further damage and scarring. We know that drugs that prevent recruitment of these immune cells to injured organs can slow, but not stop, progression of liver and kidney disease. However, some subsets of the immune cells may be beneficial as they are required for normal tissue functions and to promote repair. Hence, blocking all immune cells from reaching the damaged organ is not advisable and a more targeted approach to inhibit specifically those subsets that promote injury is likely to be more beneficial.In order to identify the specific immune cell subsets that promote organ injury, we have employed a state-of-the art technology called single-cell RNA sequencing in models of kidney and liver disease. This enabled us to determine which genes were switched on or off in individual immune cells. This revealed that there were many more immune cell subsets than we were previously aware of. By analysing the genes that are activated in each cell, we have identified a subset of immune cells that expresses many genes that promote inflammation and scarring, leading us to suspect that this subset may promote kidney and liver injury. The immune cells in this subset have a specific protein called CLEC4D on their surface and we believe that targeting this CLEC4D molecule may prevent organ injury in a more precise manner than current therapies.In this project we will use surplus tissue from biopsies from patients with liver and kidney disease to examine which molecular pathways are activated in the immune cells that express CLEC4D. This knowledge will help us develop new drugs that can prevent these cells causing inflammation and scarring. Our collaborators have developed an antibody that binds to and neutralises the action of CLEC4D. We will use pre-clinical models of kidney and liver injury to test whether this antibody prevents the activation of immune cells, thereby preventing development of scar tissue in the organs. If successful, this could be used to prevent the development of scarring in the organs of patients with kidney and liver disease.In addition, we have found a specific biochemical pathway is activated in the CLEC4D+ immune cells, which we believe contributes to inflammation and scarring. We will use genetic tools to block this pathway in the immune cells to test this hypothesis in models of kidney and liver disease. This will indicate whether blockade of this pathway by administration of a drug might be an alternative method of preventing kidney and liver scarring.In summary, our studies will determine whether a number of complementary strategies focused on inhibition of a specific subset of immune cells could reduce inflammation and scarring in organs including kidney and liver to prevent organ failure.

患有肾脏和肝脏疾病的患者失去了正常的器官组织，因为它逐渐被疤痕组织所取代，导致器官功能下降。最终，这可能导致器官衰竭，患者需要接受长期透析治疗或肾/肝移植。尽管有这些挽救生命的疗法，肾脏和肝脏疾病仍然是第11和第12大死亡原因。不幸的是，患有肾脏和肝脏疾病的患者数量持续上升，治疗选择仍然有限，因此研究人员发现减缓疾病进展的新疗法至关重要。无论损伤的根本原因是什么，肾脏和肝脏的损伤都会导致白色血细胞向受损器官募集。这些细胞是身体免疫系统的一部分，对于对抗感染很重要，但是在器官损伤期间，它们可能会促进进一步的损伤和疤痕。我们知道，阻止这些免疫细胞募集到受损器官的药物可以减缓，但不能阻止肝脏和肾脏疾病的进展。然而，免疫细胞的某些亚群可能是有益的，因为它们是正常组织功能和促进修复所必需的。因此，阻止所有免疫细胞到达受损器官是不可取的，更有针对性的方法来抑制那些促进损伤的亚群可能更有益。为了识别促进器官损伤的特定免疫细胞亚群，我们采用了最先进的技术，称为单细胞RNA测序在肾脏和肝脏疾病模型中。这使我们能够确定在单个免疫细胞中哪些基因被打开或关闭。这表明，免疫细胞亚群比我们以前知道的要多得多。通过分析每个细胞中被激活的基因，我们已经确定了一个免疫细胞亚群，它表达许多促进炎症和瘢痕形成的基因，这使我们怀疑这个亚群可能促进肾脏和肝脏损伤。这个亚群中的免疫细胞表面有一种叫做CLEC 4D的特异性蛋白质，我们相信靶向这种CLEC 4D分子可能会比目前的治疗方法更精确地预防器官损伤。在这个项目中，我们将使用来自肝脏和肾脏疾病患者活检的剩余组织来检查表达CLEC 4D的免疫细胞中哪些分子通路被激活。这些知识将帮助我们开发新的药物，可以防止这些细胞引起炎症和疤痕。我们的合作者已经开发出一种抗体，可以结合并中和CLEC 4D的作用。我们将使用肾脏和肝脏损伤的临床前模型来测试这种抗体是否会阻止免疫细胞的激活，从而防止器官中瘢痕组织的发展。如果成功的话，这可以用于预防肾脏和肝脏疾病患者器官中的瘢痕形成。此外，我们发现CLEC 4D+免疫细胞中的特定生化途径被激活，我们认为这有助于炎症和瘢痕形成。我们将使用遗传工具来阻断免疫细胞中的这一途径，以在肾脏和肝脏疾病模型中验证这一假设。这将表明通过给药阻断该途径是否可能是预防肾脏和肝脏瘢痕形成的替代方法。总之，我们的研究将确定是否有一些互补的策略，重点是抑制特定的免疫细胞亚群，可以减少炎症和瘢痕形成的器官，包括肾脏和肝脏，以防止器官衰竭。