Role of primary cilium in morphogen signalling modulation by Transforming Growth Factor-beta (TGF-beta) and its involvement in tissue fibrosis and abe

...本项目将从表观遗传、分子和细胞水平研究组织纤维化的分子基础。组织纤维化是组织再生“变坏”的结果，伴随着组织固有的成纤维细胞活化，向细胞外基质分泌大量胶原蛋白，改变组织特异性细胞类型的微环境，损害组织的功能。本项目将研究成纤维细胞活化时发生的信号转导变化的分子基础，使用硬皮病作为纤维化模型。硬皮病是一种病因不明的自身免疫性疾病，导致广泛的成纤维细胞活化，通常在皮肤中诊断，但在严重的情况下扩展到内脏器官，如肺和心脏。在从患者或健康对照中分离的成纤维细胞中发现了形态发生素Shh、Wnt和TGF-β信号传导的关键差异，并且观察到患病细胞中初级纤毛显著缩短。初级纤毛就像一个细胞天线，几个关键的受体位于其中，并且已知其形态的细微变化会导致大范围的缺陷和疾病。该项目将调查纤维化成纤维细胞的初级纤毛的形态变化是否是对维持皮肤正常解剖结构和功能的重要信号分子的缺陷反应的原因，并研究短纤毛是否是细胞群中持续存在的表观遗传变化的结果，或者它们是否容易逆转并适合治疗干预。该项目将部分在利兹大学主校区的生物科学学院进行，与Riobo-Del Galdo博士的小组在信号转导、蛋白质纯化、分子生物学、高分辨率成像和生物化学测定方面合作，部分在位于圣詹姆斯大学医院校园的Del Galdo博士实验室进行，处理患者活检、分离原代细胞、以及体外工程化多层“皮肤等同物”以研究初级纤毛和形态发生素信号传导对表皮生长和血管生成测定的影响。

...rrant wound healingThis project will investigate the molecular basis of tissue fibrosis, at the epigenetic, molecular and cellular level. Tissue fibrosis is the result of tissue regeneration 'gone bad', and is accompanied by the activation of tissue resident fibroblasts to secrete large amounts of collagen to the extracellular matrix that change the microenvironment for the tissue-specific cell types, impairing the function of the tissue.This project will study the molecular basis of changes in signal transduction that occur in fibroblasts when they undergo activation, using Scleroderma as a model of fibrosis. Scleroderma is an autoimmune disorder of unknown aetiology that results in widespread fibroblast activation, commonly diagnosed in the skin, but in severe cases extended to internal organs like lungs and heart. Key differences in signalling of the morphogens Shh, Wnt, and TGF-B have been found in fibroblasts isolated from patients or healthy controls, and a striking distinctive shortening of the primary cilium in the diseased cells has been observed. The primary cilium is like a cellular antenna where several key receptors localise, and subtle changes in its morphology have been known to cause a large range of defects and disorders. This project will investigate if the morphological change in the primary cilium of fibrotic fibroblasts is the cause of the defective response to important signalling molecules that maintain the normal anatomy and function of the skin, and study if the short cilia are the result of epigenetic changes that persist in the cell population or if they are easily reversible and amenable to therapeutic interventions. The project will be carried out partly in the Faculty of Biological Sciences in the main campus of the University of Leeds, working with Dr. Riobo-Del Galdo's group in signal transduction, protein purification, molecular biology, high resolution imaging and biochemical assays, and partly in Dr. Del Galdo's lab located in the St. James' University Hospital campus, handling patient biopsies, isolating of primary cells, and engineering in vitro multi-layered "skin equivalents" to investigate the effect of the primary cilium and morphogen signalling on epidermal growth and angiogenesis assays.