Regulation of leukocyte recruitment by fibroblast-endothelial interactions

通过成纤维细胞-内皮细胞相互作用调节白细胞募集：了解基质从溶解到持续性炎症的转换类风湿性关节炎(RA)是影响约1%英国人口残疾的主要原因。针对白细胞或其细胞因子产生的生物疗法改善了结果，但它们既不能逆转组织损伤，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对疾病的控制。RA滑膜成纤维细胞是关节损伤和疾病持久性的主要贡献者，但尚未被靶向治疗。滑膜成纤维细胞通过与排列血管的内皮细胞(EC)相互作用，主动调节白细胞的募集(McGettrack等人，2009年)。我们已经确定了一种独特的滑膜成纤维细胞的表型，这种表型在早期关节炎中可见，它将急性融解性关节炎(RES)与早期RA(ERA)区分开来。RES成纤维细胞在EC中诱导免疫抑制反应，限制招募到关节的白细胞的数量(McGettrack等人，2014；McGettrack等人，2015)。然而，这种能力在Era滑膜成纤维细胞中消失(McGettrack等人，2014；McGettrack等人，2015)。这一变化代表了滑膜成纤维细胞-内皮细胞相互作用的表型从保护性转变为病理性。这个博士生的目标是询问支持滑膜成纤维细胞和EC之间细胞间相互作用的分子机制。为了实现这一目标，学生将有机会获得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的高通量分析平台(例如，微阵列、RNAseq、蛋白质组学、磷酸酶阵列、代谢组学)、基于流动的黏附分析、活体全组织成像平台以及伯明翰提供的融合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，我们的目标是测试模仿RES SF的行为或抑制“致病”ERA或RA SF的行为是否可以重置白细胞募集的平衡，从而阻止疾病的进展。

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.