Determining how sub-cellular localisation of interleukin-1alpha regulates immunity.

确定 IL-1α 的亚细胞定位如何调节免疫。

• 批准号: BB/Y004876/1
• 负责人: Gloria Lopez-Castejon
• 金额: $ 80.83万
• 依托单位: University of Manchester
• 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=BB%2FY004876%2F1
• 关键词: Determining; how; sub; cellular; localisation

Inflammation is a response of the body to danger, such as an infection. During inflammation the immune system is activated and innate immune cells such as macrophages are alerted to remove the specific danger, for example a virus, and restore health. Inflammation is dysregulated with aging as well as during many diseases. Hence it is very important that we understand the basic mechanisms that control inflammation. Macrophages are important cells in the inflammatory process as they produce molecules that coordinate other immune cells to fight infection. The most important of these molecules are called cytokines.This project will investigate the role of the cytokine Interleukin-1alpha. This interleukin is unique, in that it has a nuclear localisation sequence, that allows it to move between the cytosol and the nucleus of the cell. We believe that this allows this cytokine to play a dual role during inflammation, and infection. First, we think trafficking to the nucleus prevents unnecessary release of this cytokine, preventing an excessive and unwanted inflammatory response. Second, we propose that interleukin-1alpha plays a role in controlling production of other molecules produced by macrophages that are important for inflammation and its resolution.To investigate these hypotheses, we have generated a mouse in which interleukin-1alpha cannot enter the nucleus allowing us to differentiate the inflammatory response from these mice, and mice that have a normal interleukin-1alpha. Also, we have established a technique to detect molecules that are very close to interleukin-1alpha and that could therefore regulate its activity. This research will uncover new ways by which this cytokine is regulated and new molecules that are important for inflammation. This will be very interesting as it will result in new knowledge on mechanisms of defence against infection that might also be applicable to other areas of research such as aging or disease.

炎症是身体对危险的反应，如感染。在炎症过程中，免疫系统被激活，先天免疫细胞如巨噬细胞被提醒清除特定的危险，如病毒，并恢复健康。炎症随着年龄的增长以及在许多疾病中失调。因此，了解控制炎症的基本机制非常重要。巨噬细胞是炎症过程中的重要细胞，因为它们产生协调其他免疫细胞对抗感染的分子。这些分子中最重要的分子被称为细胞因子。本项目将研究细胞因子白细胞介素-1 α的作用。这种白细胞介素是独特的，因为它具有核定位序列，允许它在细胞的胞质溶胶和细胞核之间移动。我们认为，这使得这种细胞因子在炎症和感染过程中发挥双重作用。首先，我们认为细胞核的运输阻止了这种细胞因子的不必要释放，防止了过度和不必要的炎症反应。其次，我们提出白细胞介素-1 α在控制巨噬细胞产生的其他分子的产生中起作用，这些分子对炎症及其消退很重要。为了研究这些假设，我们已经产生了一只白细胞介素-1 α不能进入细胞核的小鼠，使我们能够区分这些小鼠的炎症反应，以及具有正常白细胞介素-1 α的小鼠。此外，我们已经建立了一种技术来检测非常接近白细胞介素-1 α的分子，因此可以调节其活性。这项研究将揭示这种细胞因子调节的新方式和对炎症重要的新分子。这将是非常有趣的，因为它将导致对感染的防御机制的新知识，也可能适用于其他研究领域，如衰老或疾病。