Targeting Adiponectin Signaling: Novel Peptide Therapy for Scleroderma

描述（由申请人提供）：硬皮病的纤维化是由受损微环境中活化的肌成纤维细胞的积累引起的，并伴有皮下脂肪组织的损失。由于肌成纤维细胞分化具有潜在的可逆性，因此了解控制该过程的信号通路和转录分子对于开发抗纤维化治疗具有重要意义。脂肪形成的主要调节因子ppar - γ是多种器官中肌成纤维细胞分化的有效抑制剂。我们发现抑制作用是通过脂联素（ADP）介导的，ADP是一种具有多效体液和旁分泌作用的脂肪因子，主要但不完全由脂肪细胞产生。早期弥漫性硬皮病患者的皮肤活检和血清中ADP水平显著降低。这些观察结果提示了一种新的纤维化模式，将脂肪生成受损、ADP生成减少和肌成纤维细胞分化抑制联系起来。我们的假设是，脂肪萎缩和随之而来的低脂联素血症有助于硬皮病的持续纤维生成。我们预测，ADP和一流的合成肽作为ADP受体激动剂，将通过拮抗细胞内纤维化信号通路，减弱正常和硬皮病皮肤成纤维细胞的纤维化反应，并改善小鼠模型中的硬皮病。我们将i)定义ADP在正常和硬皮病成纤维细胞、3D器官型模型和硬皮病皮肤活检中的抗纤维化活性和作用机制；ii)开发新的ADP肽；iii)评估两种先导肽在预防和促进小鼠硬皮病纤维化消退中的作用。我们在这里提出的不受管制的脂肪生成和纤维化之间的机制联系在概念上是创新的。该项目影响很大，因为目前还没有批准的硬皮病治疗方法。此外，该结果将对目前缺乏有效治疗的无数纤维化疾病产生强烈影响。

DESCRIPTION (provided by applicant): Fibrosis in scleroderma results from accumulation of activated myofibroblasts in injured microenvironments, and is accompanied by loss of subcutaneous adipose tissue. Since myofibroblast differentiation is potentially reversible, understanding signaling pathways and transcription molecules controlling the process is of fundamental importance for the development of antifibrotic therapies. The master regulator of adipogenesis, PPAR-gamma, is a potent inhibitor of myofibroblast differentiation in multiple organs. We found that the inhibitory effects are mediated through adiponectin (ADP), an adipokine with pleiotropic humoral and paracrine effects produced primarily but not exclusively by fat cells. Levels of ADP were significantly reduced in skin biopsies and in serum from patients with early diffuse scleroderma. These observations suggest a novel paradigm for fibrosis linking impaired adipogenesis, reduced ADP production and unchecked myofibroblast differentiation. Our hypothesis is that adipose atrophy and consequent hypoadiponectinemia contribute to persistent fibrogenesis in scleroderma. We predict that ADP and first-in-class synthetic peptides acting as ADP receptor agonists will attenuate fibrotic responses in normal and scleroderma skin fibroblasts by antagonizing intracellular profibrotic signaling pathways, and ameliorate scleroderma in mouse models. We will i) define ADP anti-fibrotic activity and mechanism of action in normal and scleroderma fibroblasts, 3D organotypic models and scleroderma skin biopsies; ii) develop novel ADP peptides; and iii) evaluate the two lead peptides in prevention, and promoting regression of, fibrosis in murine scleroderma. The mechanistic link between deregulated adipogenesis and fibrosis we propose here is conceptually innovative. The project is high impact since there are no approved treatments for scleroderma. Moreover, the results will have a strong impact on myriad fibrosing diseases that currently lack effective treatment.