Regulation of leukocyte recruitment by fibroblast-endothelial interactions

通过成纤维细胞内皮相互作用调节白细胞募集：了解从消退到持续炎症的基质转换类风湿关节炎（RA）是影响约1%英国人残疾的主要原因。针对白细胞或其产生的细胞因子的生物治疗改善了结果，但它们不能逆转组织损伤，也不能治愈疾病。在疾病的早期阶段，常规治疗明显更有效，但其原因尚不清楚。目前的证据表明，如果我们能够更好地针对早期发生的独特病理过程，我们可能能够进一步改善疾病的控制。类风湿性关节炎滑膜成纤维细胞是关节损伤和疾病持续的主要原因，但尚未有针对性的治疗。滑膜成纤维细胞通过与血管内皮细胞（EC）的相互作用积极调节白细胞募集（McGettrick et al., 2009）。我们在早期关节炎中发现了一种独特的滑膜成纤维细胞表型，可以区分急性消退性关节炎（Res）和早期RA （eRA）。Res成纤维细胞在EC中诱导免疫抑制反应，限制了白细胞募集到关节的数量（McGettrick et al., 2014; McGettrick et al., 2015）。然而，eRA滑膜成纤维细胞失去了这种能力（McGettrick et al., 2014; McGettrick et al., 2015）。这种变化代表了从保护性到病理性滑膜成纤维细胞内皮细胞相互作用的表型转换。本博士研究生的目的是探究滑膜成纤维细胞和EC之间细胞串扰的分子机制。为了实现这一目标，学生将获得来自伯明翰早期关节炎队列（BEACON）的独特细胞材料资源，这些材料将使用诺华公司的高通量分析平台（例如微阵列、rna - eq、蛋白质组学、磷酸激酶阵列、代谢组学）、流动黏附分析、活体组织成像平台和伯明翰公司提供的包含人类滑膜组织和细胞的关节炎嵌合小鼠模型进行分析。这项工作将对疾病的发病机制产生新的见解，并为药物开发提供新的靶点。最终，我们的目标是测试是否模仿Res SF的作用或抑制“致病性”eRA或RA SF的作用可以重置白细胞募集的平衡，从而阻止疾病进展。

Regulation of leukocyte recruitment by fibroblast-endothelial interactions: Understanding the stromal switch from resolution to persistent inflammationRheumatoid arthritis (RA) is a major cause of disability affecting ~1% of the UK population. Biological treatments that target leukocytes or their cytokine produces have improved outcomes, but they do not reverse tissue damage nor do they cure disease. During the earliest stages of disease, conventional treatments are significantly more effective, but the reasons for this are not clear. Current evidence suggests that we may be able to improve control of disease further if we can better target the unique pathological processes occurring early on. RA synovial fibroblasts are major contributors to joint damage and disease persistence, but have yet to be targeted therapeutically. Synovial fibroblasts actively regulate leukocyte recruitment through interactions with endothelial cells (EC) that line blood vessels (McGettrick et al., 2009). We have characterised a unique phenotype of synovial fibroblasts seen in early arthritis that distinguishes acute resolving arthritis (Res) from the early stages of RA (eRA). Res fibroblasts induce an immunosuppressive response in EC that limits the magnitude of leukocytes recruited to the joint (McGettrick et al., 2014; McGettrick et al., 2015). However this capacity is lost in eRA synovial fibroblasts (McGettrick et al., 2014; McGettrick et al., 2015). This change represents a phenotypic swtich from protective to pathological synoival fibroblast-endothelial cell interactions. Thie aim of this PhD studentship is to interrogate the molecular mechanism underpinning the cellular cross-talk between the synovial fibroblasts and EC. To achieve this the student will have access to a unique resource of cellular material from the Birmingham Early Arthritis Cohort (BEACON), which will be analysed using high throughput analysis platforms (e.g. microarrays, RNAseq, proteomics, phosphokinase arrays, metabolomics) at Novartis, by flow based adhesion assays, live whole tissue imaging platforms, and chimeric mouse models of arthritis incorporating human synovial tissue and cells available at Birmingham. The work will generate new insights into disease pathogenesis and provide novel targets for drug development. Ultimately, we aim to test whether mimicking the actions of Res SF or inhibiting those of 'pathogenic' eRA or RA SF can reset the balance of leukocyte recruitment, thus halting disease progression.