Regulation of leukocyte recruitment by fibroblast-endothelial interactions

成纤维细胞-内皮相互作用对白细胞募集的调节

• 批准号: 2102841
• 金额: --
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2102841
• 关键词: Regulation; leukocyte; recruitment; fibroblast; endothelial

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.

通过成纤维细胞-内皮细胞相互作用调节白细胞募集：了解从消退到持续性炎症的基质转换风湿性关节炎（RA）是影响约1%英国人口的残疾的主要原因。靶向白细胞或其细胞因子产生的生物治疗具有改善的结果，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。RA滑膜成纤维细胞是关节损伤和疾病持续性的主要贡献者，但尚未被靶向治疗。滑膜成纤维细胞通过与内衬血管的内皮细胞（EC）相互作用来主动调节白细胞募集（McGettrick等人，2009年）。我们已经表征了在早期关节炎中观察到的滑膜成纤维细胞的独特表型，其将急性消退性关节炎（Res）与早期RA（eRA）区分开来。Res成纤维细胞在EC中诱导免疫抑制应答，其限制了募集到关节的白细胞的数量（McGettrick等人，2014; McGettrick等人，2015年）。然而，这种能力在eRA滑膜成纤维细胞中丧失（McGettrick等人，2014; McGettrick等人，2015年）的报告。这种变化代表了从保护性滑膜成纤维细胞-内皮细胞相互作用到病理性滑膜成纤维细胞-内皮细胞相互作用的表型转变。本博士研究的目的是探讨滑膜成纤维细胞和EC之间细胞串扰的分子机制。为了实现这一目标，学生将有机会获得来自伯明翰早期关节炎队列（BEACON）的独特细胞材料资源，这些材料将使用高通量分析平台进行分析（例如微阵列、RNAseq、蛋白质组学、磷酸激酶阵列、代谢组学），通过基于流动的粘附测定，活的全组织成像平台，和结合人滑膜组织和细胞的关节炎嵌合小鼠模型，可从Birmingham获得。这项工作将产生对疾病发病机制的新见解，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的作用或抑制“致病性”eRA或RA SF的作用是否可以重置白细胞募集的平衡，从而阻止疾病进展。