Hyaluronan (HA) assembly and its Role in Bone Morphogenic Protein-7 Driven Antagonism of Renal Fibrosis

由纤维化引起的器官衰竭是我们人口中慢性疾病的主要原因，包括肾脏疾病、肝脏疾病、肺病和心脏病。然而，目前还没有可以阻止或逆转纤维化并防止器官损伤的治疗方法。这项研究旨在确定可能缓解或逆转纤维化的靶点，目的是开发新的治疗方法来预防高危患者的终末器官损伤。肌成纤维细胞是产生纤维化的主要细胞。它们是由循环因子转化生长因子-β1通过转化上皮细胞和成纤维细胞而产生的。BMP7是另一种循环因子，它反对转化生长因子-β-1驱动的纤维化。然而，无论是直接阻断转化生长因子-β1，还是使用BMP7治疗，都不是可行的治疗方法，因为它们会产生显著的副作用。因此，我们需要进一步研究这两个循环因素，以确定更有针对性的治疗方法，副作用更少。我们的部门之前已经证明，转化生长因子-β-1驱动的肌成纤维细胞的形成依赖于细胞如何制造和组装第三个分子--透明质酸(HA)。我们还知道，BMP7可以组装不同于转化生长因子-β-1的HA。我们的目标是进行详细的研究，以确定BMP-7对成纤维细胞/上皮细胞如何产生、组装和处理HA的影响；从而使我们能够区分好的和坏的HA。这将使我们能够防止肌成纤维细胞的形成，从而使我们能够确定可以预防或逆转高危患者纤维化的治疗方法。

Organ failure resulting from fibrosis is the predominant cause of chronic diseases in our population including kidney disease, liver disease, lung and heart disease. However no treatments exist that can halt or reverse fibrosis and prevent organ damage. This research aims to identify targets that can potentially alleviate or reverse fibrosis, with the aim of developing new therapies to prevent end-organndamage in at-risk patients.Myofibroblast are the principle fibrosis-producing cells. They are produced by the circulating factor TGF-beta-1 through transformation of epithelial cells and fibroblasts. BMP7 is another circulating factor, which opposes TGF-beta-1-driven fibrosis. However, neither direct blocking of TGF-beta-1, nor treatment with BMP7 are viable therapies as they cause significant side effects. Thus we need to further study these two circulating factors to identify more targetted therapy with less side effects. Our department has previously shown that TGF-beta-1-driven formation of myofibroblasts is dependent on how cells make and assemble a third molecule, Hyaluronan (HA). We also know that BMP7 can assemble HA differently to TGF-beta-1. Our aim is to carry out detailed studies to determine the effects of BMP-7 on how fibroblasts/epithelial cells generate, assemble and handle HA; thus allowing us to differentiate between good and bad HA. This will allow us to prevent formation of myofibroblasts, thus enabling us to identify therapies that can prevent or reverse fibrosis in at risk patients.