Investigating the role of synovial glycome in the interplay between systemic and joint inflammation.

研究滑膜糖组在全身炎症和关节炎症之间相互作用中的作用。

• 批准号: MR/Y003551/1
• 负责人: Miguel Pineda
• 金额: $ 67.51万
• 依托单位: University of Glasgow
• 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=MR%2FY003551%2F1
• 关键词: Investigating; role; synovial; glycome; interplay

Normal inflammation is needed for fighting infections, but when this process becomes uncontrolled, it can last for months or even years, leading to severe chronic conditions. Cardiovascular disease, cancer, diabetes, chronic kidney disease, neurodegenerative disorders, and a large group of autoimmune conditions, like Rheumatoid Arthritis (RA) are only a few examples. (RA) is an extended chronic inflammatory disease, causing pain, stiffness, and swelling on the body's joint. However, RA affects not only the joints, as inflammation also affects some patients in areas as diverse as the eyes, gut, skin, or heart. Why some people suffer from these non-joint pathologies, and some others do not, is unknown. There are many biological mechanisms described in RA, and we still do not fully understand the genetic and environmental factors that contribute to the activation of these disease-leading routes. As a result, not all the drugs work for all people and clinicians must follow a trial-and-error approach. Furthermore, reliable diagnostic features that can be used to measure disease progression and outcomes have not yet been determined.Our objective is to investigate how chronic inflammation is consolidated, with a special focus on the mechanisms leading to disease variability and inflammation in multiple organs. Based on our preliminary results, we think that different kinds of inflammation are a consequence of unbalanced expression of glycans, a specific type of molecules found in all cells and organs in the body. Glycans, or complex sugars, are expressed on all cell surfaces. Due to this privileged location, they are a fundamental part of any process involved in cell communication, including inflammation. We have previously discovered that joint inflammation is increased when glycans are modified by inflammatory mediators. Building on these results, we have formulated the hypothesis that specific changes in glycan composition can induce different inflammatory routes, which in turn, can start disease in other organs. Our goal is to validate this hypothesis in human RA and identify how glycan changes in the joint of patients can induce inflammation in other parts of the body. We plan to achieve this goal by exploiting the clinical diversity observed in RA. Samples will be obtained from joint replacement surgery, in which we will analyze the glycan composition. Blood samples will be also collected to correlate glycan expression with general inflammation away from the joint. We will correlate molecular details (glycan structure, inflammatory factors) with clinical parameters (type of inflammation, inflamed organs). Understanding the molecular details of distinct inflammatory glycans will allow us to find predictive markers to apply the right treatment, to the right person, at the right time. We expect to generate new ideas to better understand inflammation, something that can benefit not only people with arthritis, but also many other patients suffering from other chronic inflammatory and autoimmune disorders. Although glycans have been overlooked in research due to their complexity, recent technological advances, like some of the techniques to be used in our project, have clearly demonstrated that these molecules are at the center of many diseases, sparking the possibility of using them for therapeutic and diagnostic purposes.The project will be conducted by a multidisciplinary team, including clinicians, biologists, and chemists to explore new ideas involving academic institutions and NHS hospitals and clinics in Glasgow, Birmingham, and London. Together, we aim to find answers to unsolved challenges using an overlooked area of human health, which will reveal new methods to identify effective medical interventions.

正常的炎症是对抗感染所必需的，但是当这个过程变得不受控制时，它可以持续数月甚至数年，导致严重的慢性疾病。心血管疾病、癌症、糖尿病、慢性肾脏疾病、神经退行性疾病和一大群自身免疫性疾病，如风湿性关节炎（RA）只是几个例子。(RA)是一种长期慢性炎症性疾病，引起疼痛，僵硬，和身体的关节肿胀。然而，RA不仅影响关节，因为炎症也影响一些患者的眼睛，肠道，皮肤或心脏等不同区域。为什么有些人患有这些非关节病变，而有些人没有，是未知的。RA中描述了许多生物学机制，我们仍然没有完全了解导致这些疾病导致途径激活的遗传和环境因素。因此，并非所有的药物对所有人都有效，临床医生必须遵循试错法。此外，可用于衡量疾病进展和结果的可靠诊断特征尚未确定。我们的目标是研究慢性炎症是如何巩固的，特别关注导致疾病变异性和多器官炎症的机制。根据我们的初步结果，我们认为不同类型的炎症是聚糖表达不平衡的结果，聚糖是一种在体内所有细胞和器官中发现的特定类型的分子。聚糖或复合糖在所有细胞表面上表达。由于这种特殊的位置，它们是细胞通讯（包括炎症）所涉及的任何过程的基本组成部分。我们先前已经发现，当聚糖被炎症介质修饰时，关节炎症增加。在这些结果的基础上，我们提出了一个假设，即聚糖组成的特定变化可以诱导不同的炎症途径，进而可以在其他器官中引发疾病。我们的目标是在人类RA中验证这一假设，并确定患者关节中的聚糖变化如何诱导身体其他部位的炎症。我们计划通过利用在RA中观察到的临床多样性来实现这一目标。样本将从关节置换手术中获得，我们将在手术中分析聚糖组成。还将采集血液样本，以将聚糖表达与远离关节的一般炎症相关联。我们将分子细节（聚糖结构，炎症因子）与临床参数（炎症类型，发炎器官）相关联。了解不同炎症性聚糖的分子细节将使我们能够找到预测标记，以便在正确的时间对正确的人进行正确的治疗。我们希望产生新的想法来更好地了解炎症，这不仅可以使关节炎患者受益，还可以使许多患有其他慢性炎症和自身免疫性疾病的患者受益。虽然聚糖由于其复杂性而在研究中被忽视，但最近的技术进步，如我们项目中使用的一些技术，已经清楚地表明这些分子是许多疾病的中心，引发了将其用于治疗和诊断目的的可能性。该项目将由一个多学科团队进行，包括临床医生，生物学家，和化学家探索新的想法，涉及学术机构和国民保健服务的医院和诊所在格拉斯哥，伯明翰，和伦敦。我们的目标是共同利用人类健康的一个被忽视的领域，为尚未解决的挑战找到答案，这将揭示识别有效医疗干预措施的新方法。