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Targeting Adiponectin Signaling: Novel Peptide Therapy for Scleroderma

靶向脂联素信号传导：硬皮病的新型肽疗法

基本信息

批准号：
8712364
负责人：
John Varga
金额：
$ 16.4万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-02 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8712364
关键词：
Adipocytes Adipose tissue Affect Agonist Atrophic Attenuated Biopsy Bleomycin Blood Circulation Cells Cessation of life Chronic Chronic Disease Cicatrix Clinical Treatment Clinical Trials Collagen Dermal Development Diffuse Scleroderma Disease Disease Progression Family Fibroblasts Fibrosis Future Gene Expression Genetic Programming Genetic Transcription Goals Hormones Human In Vitro Lead Link Mediating Medical Mesenchymal Modeling Molecular Profiling Mus Myofibroblast Organ Outcome PPAR gamma Pathway interactions Patients Peptides Peroxisome Proliferator-Activated Receptors Pharmaceutical Preparations Phase Physiological Pre-Clinical Model Prevention Process Production Property Role Scleroderma Serum Severity of illness Signal Pathway Signal Transduction Skin Staging Testing Therapeutic Tissues Validation adenylate kinase adiponectin base design disability effective therapy fibrogenesis genome-wide in vivo inhibitor/antagonist injured innovation lipid biosynthesis member mimetics mortality mouse model novel paracrine prevent public health relevance receptor response subcutaneous synthetic peptide

项目摘要

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.

描述(由申请人提供)：硬皮病的纤维化是由受损微环境中激活的肌成纤维细胞积聚引起的，并伴随着皮下脂肪组织的丢失。由于肌成纤维细胞分化可能是可逆的，了解控制这一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。脂肪生成的主要调节因子PPAR-γ是一种有效的多器官肌成纤维细胞分化的抑制因子。我们发现，这种抑制作用是通过脂联素(ADP)介导的，ADP是一种脂肪因子，具有多效性体液和旁分泌作用，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的ADP水平显著降低。这些观察提示了一种新的纤维化模式，将脂肪生成受损、ADP产生减少和肌成纤维细胞分化不受抑制联系在一起。我们的假设是脂肪萎缩和随之而来的低脂联素血症导致硬皮病的持续性纤维化。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促纤维化信号通路来减弱正常和硬皮病皮肤成纤维细胞的纤维化反应，并改善小鼠模型的硬皮病。我们将i)确定ADP在正常和硬皮病成纤维细胞、3D器官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多肽；以及iii)评价这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。我们在这里提出的放松调控的脂肪形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，因为目前还没有获得批准的治疗硬皮病的方法。此外，这一结果将对目前缺乏有效治疗的无数纤维性疾病产生强烈影响。