Interrogating NRK1 activity as a central regulator of CD4+ T cell metabolism, fate and function

探究 NRK1 活性作为 CD4 T 细胞代谢、命运和功能的中心调节因子

• 批准号: MR/V011588/1
• 负责人: Sarah Dimeloe
• 金额: $ 84.37万
• 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: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV011588%2F1
• 关键词: Interrogating; NRK1; activity; central; regulator

T cells are a critical part of our immune system which co-ordinate the activity of all other immune cells (white blood cells) to protect us from infections and cancer. However, sometimes T cells can be over-active, which can be harmful. When this occurs it can cause diseases such as rheumatoid arthritis, multiple sclerosis and diabetes. These are known as inflammatory or autoimmune diseases, a process where the body's own immune cells attack it. Current therapies for these diseases do not always work well, meaning that many patients still suffer with severe symptoms and these diseases still place a significant burden on the NHS.In the last decade our understanding of how T cells work has been transformed. We have learned that the activity of T cells is very tightly linked to a series of chemical processes known as metabolism, which occurs in every cell of the human body. These processes are used to break down nutrients such as sugar to provide energy and building blocks for the cell. Recent research has revealed that T cells can dramatically change how they break down nutrients when they carry out their protective (normal activity) or harmful (over-active) functions. Studies in patients with infectious and autoimmunity have revealed that these processes are often abnormal in T cells in these conditions. It may be possible therefore, that with new drugs that correct these changes in metabolism, we can restore normal, safe T cell activity, and better treat these diseases.This proposal will investigate one possible pathway to control T cell metabolism and restore their normal function. Specifically, I propose to test how the production of a molecule called nicotinamide adenine dinucleotide (NAD) is linked to T cell metabolism and their protective and harmful activity. NAD is produced from vitamin B3 and is required for all stages of the breakdown of sugar and other nutrients in cells. It has already identified that when T cells are activated (switched on) in the laboratory, they turn on an enzyme called NRK1 which plays an important role in making NAD from vitamin B3. Additionally, when NRK1 is not active, T cells have much lower rates of metabolism and produce much less of certain key immune signals. I now propose to build on these observations to understand in much more depth precisely how NRK1 controls T cell activity. As part of this project I will also change NRK1 activity in T cells in laboratory models of infection and autoimmunity. This will help us to test whether new drugs targeting this molecule might be helpful in these conditions.

T细胞是我们免疫系统的重要组成部分，它协调所有其他免疫细胞(白血球)的活动，以保护我们免受感染和癌症。然而，有时T细胞可能过度活跃，这可能是有害的。当这种情况发生时，它会导致类风湿性关节炎、多发性硬化症和糖尿病等疾病。这些疾病被称为炎症性疾病或自身免疫性疾病，这是人体自身免疫细胞攻击它的过程。目前治疗这些疾病的方法并不总是有效的，这意味着许多患者仍然有严重的症状，这些疾病仍然给NH带来很大的负担。在过去的十年里，我们对T细胞如何工作的理解已经改变。我们已经了解到，T细胞的活动与一系列称为新陈代谢的化学过程密切相关，这一过程发生在人体的每一个细胞中。这些过程被用来分解糖等营养物质，为细胞提供能量和积木。最近的研究表明，T细胞在发挥保护性(正常活动)或有害(过度活跃)功能时，可以极大地改变它们分解营养物质的方式。对感染性和自身免疫性疾病患者的研究表明，在这些情况下，T细胞的这些过程通常是异常的。因此，有可能利用纠正这些代谢变化的新药，我们可以恢复正常、安全的T细胞活动，并更好地治疗这些疾病。这项建议将探索一种可能的途径来控制T细胞代谢，恢复其正常功能。具体地说，我建议测试一种名为烟酰胺腺嘌呤二核苷酸(NAD)的分子的产生是如何与T细胞新陈代谢及其保护和有害活动有关的。NAD是由维生素B3产生的，是细胞中糖和其他营养物质分解的所有阶段所必需的。它已经确定，当T细胞在实验室中被激活(打开)时，它们会打开一种名为NRK1的酶，这种酶在从维生素B3合成NAD的过程中发挥着重要作用。此外，当NRK1不活跃时，T细胞的代谢率要低得多，产生的某些关键免疫信号也要少得多。我现在建议在这些观察的基础上更深入地了解NRK1是如何控制T细胞活动的。作为这个项目的一部分，我还将在感染和自身免疫的实验室模型中改变T细胞中NRK1的活性。这将有助于我们测试针对这种分子的新药是否对这些条件有帮助。