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）：硬皮病中的纤维化是由于受伤的微环境中激活的肌纤维细胞积累而导致的，并伴随着皮下脂肪组织的损失。由于肌纤维细胞的分化可能是可逆的，因此了解控制该过程的信号通路和转录分子对于抗纤维化疗法的发展至关重要。脂肪生成的主要调节剂PPAR-GAMMA是多个器官中肌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，脂联素（ADP）是一种具有多效性体液和旁分泌作用的脂肪因子，主要产生但不完全由脂肪细胞产生。皮肤活检和血清中早期弥漫性硬皮病患者的血清中的ADP水平显着降低。这些观察结果表明，纤维化有一个新的范式，将脂肪生成受损，ADP产生减少和未检查的肌纤维细胞分化联系起来。我们的假设是，脂肪萎缩和随之而来的低磷灰负症有助于硬皮病中持续的纤维发生。我们预测，充当ADP受体激动剂的ADP和一流的合成肽将通过拮抗细胞内纤维细胞的正常和硬皮病皮肤成纤维细胞中的纤维化反应，通过拮抗细胞内纤维化信号途径，以及在小鼠模型中的落后硬化症。我们将）定义ADP抗纤维化活性和正常和硬皮细胞成纤维细胞，3D器官模型和硬皮病皮肤活检的作用机理； ii）开发新型的ADP肽； iii）评估鼠硬皮病中纤维化的预防中的两个铅肽。我们在这里提出的放松管制的脂肪形成与纤维化之间的机械联系在概念上是创新的。该项目的影响很大，因为没有批准的硬皮病治疗方法。此外，结果将对目前缺乏有效治疗的众多纤维疾病产生重大影响。