The role of tumour necrosis factor superfamily receptors and the innate immune system in liver inflammation and epithelial to mesenchymal transition

肿瘤坏死因子超家族受体和先天免疫系统在肝脏炎症和上皮间质转化中的作用

• 批准号: BB/E017096/1
• 负责人: Simon Afford
• 金额: $ 48.86万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FE017096%2F1
• 关键词: role; tumour; necrosis; factor; superfamily

As a consequence of its physiological functions the liver is exposed to a wide variety of pathogens and toxic insults. Consequently it is capable of protecting itself against infections entering from the blood by mounting a vigorous immune response. The earliest response triggered is called the 'innate immune response' and this is very old in evolutionary terms. We believe that this response will be critical in determining the outcome of liver damage. Such responses may be effective at removing the infectious organism but in the process may cause 'collateral' damage to the liver and to counteract this the liver can regenerate and thereby restore normal tissue architecture and function. If the balance between the immune response and the repair response is not carefully controlled the result is persistent, irreversible tissue damage, scarring and eventually cancerous change. The liver cell types most commonly targetted in these process, hepatocytes and cholangiocytes contribute to persistent damage by secreting factors that promote continuing activation of the immune system which leads to more damage and eventually to the development of a cancerous transformation of the liver cells. We propose that a family of proteins called tumour necrosis factor receptors found on the surface of liver cells are critical in determining whether injury results in removal of the injurious factor, regeneration, repair and full recovery or continuing damage, scarring and cancerous change. These receptors are activated by specific factors (ligands) in the local environment and the outcone of such activation is important for a wide range of cell functions including determining whether a cell dies or proliferates. If a cell continues in the proliferative state control is lost and it can become a cancerous cell. Thus how, when and where these receptors are activated will determine the balance between resolution/regeneration on one hand and persistent damage and cancerous change on the other. We have developed techniques to grow human cells out of liver tissue that is removed during liver transplantation allowing us to set up systems to study these processes using human liver cells rather than relying on animal models which do not always accurately represent what takes place in humans. We shall now use the human cells in tissue culture to investigate how the tumour necrosis factor receptors (TNFr) determine the balance between liver damage and repair and their involvement in cancerous change in the liver. We plan to carry out specific experiments to determine a) the factors that control whether TNF receptors are present in the liver b) how these receptors control the fate of liver cells c) how the 'innate' immune system can activate these processes. d) whether this response can lead to cancerous change in liver cells These studies will tell us a great deal about how the liver responds to injury and the role of the innate immune system in this process. The results will not only provide new information on how the normal liver functions and responds to damage but may also suggest new approaches to developing therapies in which the liver response to injury can be manipulated in favour of regeneration and repair without risking cancerous change.

作为其生理功能的结果，肝脏暴露于各种各样的病原体和毒性损伤。因此，它能够通过产生强烈的免疫反应来保护自己免受从血液进入的感染。最早触发的反应被称为“先天免疫反应”，这在进化方面非常古老。我们认为，这种反应将是决定肝损伤的结果至关重要。这样的反应可以有效地去除感染性生物体，但在此过程中可能会对肝脏造成“附带”损伤，为了抵消这种损伤，肝脏可以再生，从而恢复正常的组织结构和功能。如果免疫反应和修复反应之间的平衡不被仔细控制，结果是持续的，不可逆的组织损伤，疤痕和最终的癌变。在这些过程中最常靶向的肝细胞类型，肝细胞和胆管细胞通过分泌促进免疫系统持续激活的因子而导致持续性损伤，这导致更多损伤并最终导致肝细胞的癌性转化的发展。我们提出，在肝细胞表面发现的一种称为肿瘤坏死因子受体的蛋白质家族在确定损伤是否导致有害因子的去除、再生、修复和完全恢复或持续损伤、瘢痕形成和癌变方面至关重要。这些受体被局部环境中的特定因子（配体）激活，并且这种激活的外锥对于广泛的细胞功能（包括确定细胞是否死亡或增殖）是重要的。如果细胞继续处于增殖状态，则失去控制，并且它可能成为癌细胞。因此，如何，何时以及在何处激活这些受体将决定一方面的分辨率/再生与另一方面的持续损伤和癌变之间的平衡。我们已经开发出从肝移植过程中去除的肝组织中生长人类细胞的技术，使我们能够建立使用人类肝细胞研究这些过程的系统，而不是依赖于动物模型，这些模型并不总是准确地代表人类发生的事情。我们现在将在组织培养中使用人类细胞来研究肿瘤坏死因子受体（TNFr）如何决定肝损伤和修复之间的平衡以及它们在肝脏癌变中的参与。我们计划进行特定的实验来确定a）控制TNF受体是否存在于肝脏中的因素B）这些受体如何控制肝细胞的命运c）“先天”免疫系统如何激活这些过程。d）这种反应是否会导致肝细胞的癌变这些研究将告诉我们很多关于肝脏如何对损伤做出反应以及先天免疫系统在这一过程中的作用。这些结果不仅将提供有关正常肝脏功能和对损伤的反应的新信息，而且还可能提出开发治疗方法的新方法，其中肝脏对损伤的反应可以被操纵，有利于再生和修复，而不会有癌变的风险。