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，例如感染。在炎症期间，免疫系统被激活，并提醒先天免疫细胞（例如巨噬细胞）去除特定的危险，例如病毒并恢复健康。炎症因衰老和许多疾病而失调。因此，我们了解控制炎症的基本机制非常重要。巨噬细胞在炎症过程中是重要细胞，因为它们产生了协调其他免疫细胞以抵抗感染的分子。这些分子中最重要的人称为细胞因子。该项目将研究细胞因子白介素-1alpha的作用。该白细胞介素是独特的，因为它具有核定位序列，可以使其在细胞的细胞质和细胞核之间移动。我们认为，这使该细胞因子在炎症和感染过程中可以发挥双重作用。首先，我们认为对核的运输可以防止这种细胞因子不必要释放，从而阻止了过度和不必要的炎症反应。其次，我们提出，白素1αα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分辨率很重要。要研究这些假设，我们已经产生了一只小鼠，其中列介素1α不能输入核，使我们能够使我们能够从这些幼体和菌群中区分炎症症状，并使这些核心与已正常的小鼠区分炎症。同样，我们已经建立了一种技术来检测非常接近白介素 - 钙的分子，因此可以调节其活性。这项研究将揭示该细胞因子受调节的新方法，并且对炎症很重要的新分子。这将非常有趣，因为这将导致有关防御感染机制的新知识，这也可能适用于其他研究领域，例如衰老或疾病。