The role of X-linked inhibitor of apoptosis protein (XIAP) in Systemic Sclerosis and other fibrosing disorders

纤维化病症包括以细胞外基质（ECM）在不同器官中的广泛积累为特征的多种疾病。ECM的过度积累破坏组织结构并导致器官功能障碍。纤维化疾病的发病率不断增加，其发病率和死亡率高，缺乏有效的抗纤维化疗法，导致对靶向抗纤维化疗法的医疗需求非常高。系统性硬化症（SSc）是一种典型的系统性纤维化疾病。在风湿性疾病中，SSc的特征是最高的病例相关死亡率。弥漫性皮肤型的10年生存率低至60%。肌成纤维细胞是纤维化组织重塑的关键细胞。在正常伤口愈合中，肌成纤维细胞在肉芽组织中短暂出现，并在消退期消失。相反，肌成纤维细胞持续纤维化并维持持续的修复反应。导致肌成纤维细胞持续存在的机制还不完全清楚。虽然已经鉴定了单个的、中枢促纤维化途径，例如TGF β和WNT/β-连环蛋白信号传导，但是这些途径的伴随上调的后果及其串扰的特征还不完全。我们在初步数据中提供了第一个证据，表明XIAP可能是SSc等纤维化疾病中成纤维细胞活化的关键调节因子。我们证明，XIAP是上调成纤维细胞参与皮肤的SSc患者，特别是在患者进行性疾病，并在实验模型的SSc。TGF β 1诱导XIAP的表达。XIAP的失活在体外抑制成纤维细胞向肌成纤维细胞的转化和胶原蛋白释放，并在体内改善博来霉素诱导的皮肤纤维化。XIAP失活的抗纤维化作用可能是由于其对WNT/β-连环蛋白信号传导的抑制作用，这对于组织纤维化是足够的和必需的。总之，我们的初步数据提供了XIAP是SSc中成纤维细胞活化的中心调节因子的证据，因为它维持两个核心纤维化途径（TGF β途径和WNT/β-连环蛋白信号传导）之间的促纤维化前馈环。靶向XIAP提供了一种改善这种前馈回路并靶向纤维化疾病中的成纤维细胞活化的方法。通过本申请，我们旨在进一步分析：介导TGF β诱导XIAP的分子机制，XIAP抑制对活化的成纤维细胞表型的影响，XIAP调节WNT/β-连环蛋白信号传导的分子机制，XIAP在SSc的其他临床前纤维化模型中的纤维化疾病中的作用，以及XIAP在除SSc之外的其他纤维化疾病的发病机制中的作用。

Fibrosing disorders include multiple diseases that are characterized by the extensive accumulation of extracellular matrix (ECM) in different organs. The excessive accumulation of ECM disrupts the tissue architecture and leads to organ dysfunction. The growing incidence of fibrosing disorders, their high morbidity and mortality and the lack of effective antifibrotic therapies result in a very high medical need for targeted antifibrotic therapies. Systemic Sclerosis (SSc) is a prototypical systemic fibrotic disease. SSc is characterized by the highest case-related mortality among the rheumatic diseases. The 10-year survival is as low as 60% in the diffuse cutaneous forms. Myofibroblasts are key cells in fibrotic tissue remodeling. In normal wound healing, myofibroblasts occur transiently in the granulation tissue and disappear during the resolution phase. In contrast, myofibroblasts persist in fibrosis and maintain continuous repair responses. The mechanisms leading to the persistence of myofibroblasts are incompletely understood. Although individual, central profibrotic pathways such as TGFß and WNT/ß-catenin signaling have been identified, the consequences of the concomitant upregulation of these pathways and their crosstalk are incompletely characterized. We provide in our preliminary data first evidence that XIAP might be a pivotal regulator of fibroblast activation in fibrotic disorders such as SSc. We demonstrate that XIAP is upregulated in fibroblasts of involved skin of SSc patients, in particular in patients with progressive disease, and in experimental models of SSc. TGFß induces the expression of XIAP. Inactivation of XIAP inhibits fibroblast-to-myofibroblast transition and collagen release in vitro and ameliorates bleomycin-induced skin fibrosis in vivo. The antifibrotic effects of XIAP inactivation may result from its inhibitory effects on WNT/ß-catenin signaling, which is sufficient and required for tissue fibrosis. In summary, our preliminary data provide evidence that XIAP is a central regulator of fibroblast activation in SSc, as it sustains a profibrotic feed-forward loop between two core fibrotic pathways, the TGFß pathway and WNT/ß-catenin signaling. Targeting XIAP offers a way to ameliorate this feed-forward loop and to target fibroblast activation in fibrotic diseases. With the current application we aim to further analyze: the molecular mechanisms that mediate the induction of XIAP by TGFß, the effects of XIAP inhibition on the activated fibroblast phenotype, the molecular mechanisms by which XIAP regulates WNT/ß-catenin signaling, the role of XIAP in fibrotic disease in additional preclinical fibrosis models of SSc and the role of XIAP in the pathogenesis of other fibrotic diseases in addition to SSc.