The role of Rab46 in immune-mediated inflammatory diseases

炎症是身体试图保护我们免受感染和伤害的重要防御机制。然而，不适当的炎症，其中免疫系统是活跃的损伤后很长一段时间，在许多慢性疾病中发挥作用，包括类风湿性关节炎，牛皮癣和动脉粥样硬化。经常易患慢性炎症的人患有不止一种疾病，这表明可能有一种共同的机制触发免疫细胞不适当地发挥作用。许多免疫细胞含有称为颗粒的特殊储存包，这些颗粒在受到刺激（例如损伤）时迅速释放其内容物，以产生修复。这些内容物的释放受到高度调节，但异常释放与许多炎症性疾病相关。Rab 46是一种新的蛋白质，我们知道它在细胞释放颗粒状内容物中起着重要作用，这些细胞像肥大细胞一样对损伤迅速做出反应。此外，Rab 46基因的变异与以炎性病症为特征的疾病相关。因此，在这项研究中，我们的目的是研究Rab 46对免疫细胞释放内容物的贡献，并确定这种蛋白质的损伤是否在慢性炎症中常见。 我们将使用三种不同的方法来研究Rab 46：首先，英国生物银行中存储了超过50万名患者的遗传和健康数据。对数千名患者（例如类风湿性关节炎患者）的基因分析将告诉我们Rab 46基因的变异是否与炎症性疾病有关。第二，我们有一个特殊的患者群体，他们的肥大细胞（一组特定的免疫细胞参与过敏）对刺激过敏，并且很容易释放其内容物（肥大细胞激活综合征：MCAS）。在大约50%的MCAS患者中，根本原因未知。我们知道Rab 46在这些细胞中表达;因此，我们将对MCAS患者的遗传物质进行测序，并将Rab 46基因的遗传变异与对照组进行比较。第三，我们将确定Rab 46如何调节颗粒在肥大细胞中的流动性，通过使用显微镜比较从野生型小鼠中提取的肥大细胞中的颗粒动力学，从Rab 46基因已被删除的小鼠中提取的那些。这些研究将为我们提供数据，以确定Rab 46是否是开发新疗法的合适靶点和/或可用作诊断工具来测量获得慢性炎症性疾病的概率。

Inflammation is an essential defense mechanism by which the body tries to protect us from infection and injury. However, inappropriate inflammation, where the immune system is active long after the injury has gone, plays a role in many chronic diseases, including rheumatoid arthritis, psoriasis and atherosclerosis. People, who are susceptible to chronic inflammation often, have more than one disease, which suggests there may be a common mechanism that triggers immune cells to act inappropriately. Many immune cells contain special storage packages called granules, which rapidly release their contents upon stimulation (e.g. injury), in order to generate repair. Release of these contents is highly regulated but aberrant release is associated with many inflammatory-based diseases. Rab46 is a new protein that we know plays important roles in the release of granular contents in cells that, like mast cells, respond rapidly to injury. In addition, variations in the Rab46 gene have been associated with diseases characterized by inflammatory conditions. Therefore, in this study, we aim to investigate the contribution of Rab46 to the release of contents from immune cells and determine if impairment of this protein is common in chronic inflammation. We will investigate Rab46 using three distinct approaches: First, there is a resource of genetic and health data from over 500,000 patients stored in the UK Biobank. Genetic analysis of thousands of patients, for example with rheumatoid arthritis, will inform us if variations in the Rab46 gene is common to inflammatory disease. Second, we have a special cohort of patients whose mast cells (a specific set of immune cells involved in allergies) are hypersensitive to stimulation and release their contents too readily (Mast Cell Activation Syndrome: MCAS). In approximately 50% of patients with MCAS, the underlying cause is unknown. We know Rab46 is expressed in these cells; thereby we will sequence the genetic material of MCAS patients and compare genetic variations in the Rab46 gene with control groups. Thirdly, we will determine how Rab46 regulates granule mobility in mast cells by using microscopy to compare granule dynamics in mast cells extracted from wild-type mice to those extracted from mice where the Rab46 gene has been deleted. These studies will provide us with data to determine if Rab46 is an appropriate target for the development of novel therapeutics and/or could be utilized as a diagnostic tool to measure the probability of acquiring chronic inflammatory diseases.