Adipokine Modulation of Fibrosis: Novel Scleroderma Pathway

 描述(申请人提供)：系统性硬化症(SSC)纤维化的发病机制尚不清楚，缺乏有效的治疗方法。最近的发现指出了脂肪组织(AT)、脂肪因子和纤维化之间以前未被认识到的复杂关系。AT是多能间充质祖细胞和脂肪细胞的重要储存库，这些脂肪细胞分泌具有促纤维化和抗纤维化旁分泌活性的脂肪因子。在硬皮病小鼠模型中，真皮内血管紧张素转换酶的缺失与真皮纤维化有关，并且先于硬皮病模型的真皮纤维化，这表明它是发病机制中的主要事件。作为对成脂主要调控因子PPAR-γ的响应，AT分泌大量的脂联素。我们的初步结果显示，SSC患者血清和皮肤中的脂联素水平降低，且与皮肤评分呈负相关。脂联素有很强的抗纤维化作用，并能介导 PPAR-γ在成纤维细胞中的有益作用，而脂联素在小鼠体内的丢失会导致纤维化加剧。我假设脂联素功能受损会导致SSc持续的低脂联素状态，从而导致成纤维细胞的激活和皮肤纤维化的进展。此外，我假设脂联素是一种新的纤维化生物标记物。 也是一个潜在的治疗目标。在这项建议中，我将研究脂联素功能增强如何调节转基因小鼠的实验性纤维化；以及ii)评估具有良好特征的SSC患者队列中血清和组织脂联素水平的临床相关性。这些结果将有助于更好地理解纤维化，并表明在特定的SSC患者亚群中增加脂联素是否可能是一种潜在的治疗方法。

 DESCRIPTION (provided by applicant): The pathogenesis of fibrosis in systemic sclerosis (SSc) is poorly understood and effective treatments are lacking. Recent findings point to a previously unappreciated complex relationship between adipose tissue (AT), adipokines and fibrosis. AT is an important reservoir of both multipotent mesenchymal progenitor cells, and adipocytes secreting adipokines with pro- and anti-fibrotic paracrine activities. Loss of intradermal AT is associated with dermal fibrosis in SSc and precedes dermal fibrosis in mouse models of scleroderma, suggesting that it is a primary event in pathogenesis. In response to the adipogenic master regulator PPAR-gamma, AT secretes copious amounts of adiponectin. Our preliminary results showed reduced levels of adiponectin in the serum and skin in SSc, and an inverse correlation with skin score. Adiponectin has potent anti-fibrotic effects, and mediates the salutary effects of PPAR-gamma in fibroblasts, whereas loss of adiponectin in the mouse results in exacerbated fibrosis. I hypothesize that impaired adiponectin function results in persistent hypoadiponectinemic state in SSc that contributes to unchecked fibroblast activation and progression of skin fibrosis. Further, I hypothesize that adiponectin is a novel fibrosis biomarker and a potential target for therapy. In this proposal I will i) examine how adiponectin gain-of-function modulates experimental fibrosis in transgenic mice; and ii) evaluate the clinical correlates of serum and tissue adiponectin levels in well-characterized SSc patient cohorts. These results will contribute to a better understanding of fibrosis, and indicate if augmenting adiponectin in specific SSc patient subsets may be a potential approach to therapy.