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

这个项目将从表观遗传学、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，伴随着组织内成纤维细胞的激活，向细胞外基质分泌大量的胶原，从而改变组织特定细胞类型的微环境，损害组织的功能。本项目将以硬皮病为纤维化模型，研究成纤维细胞在激活时信号转导变化的分子基础。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激活，通常在皮肤诊断，但在严重情况下会蔓延到肺和心脏等内部器官。在从患者或健康对照分离的成纤维细胞中发现了形态致病因子Shh、Wnt和转化生长因子-β信号的关键差异，并观察到病变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这里，其形态上的细微变化已被认为会导致广泛的缺陷和紊乱。该项目将调查成纤维细胞初级纤毛的形态变化是否是对维持皮肤正常解剖和功能的重要信号分子反应缺陷的原因，并研究短纤毛是否是持续存在于细胞群体中的表观遗传变化的结果，或者它们是否容易逆转和易于治疗干预。该项目将部分在利兹大学主校区的生物科学系进行，与Riobo-Del Galdo博士的团队在信号转导、蛋白质纯化、分子生物学、高分辨率成像和生化分析方面进行合作，部分在Del Galdo博士位于圣詹姆斯大学医院校园的实验室进行，处理患者活组织，分离原细胞，并在体外设计多层“皮肤等效物”，以研究初级纤毛和形态原信号对表皮生长和血管生成分析的影响。

...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.