Experimental models of scleroderma pathogenesis

硬皮病发病机制的实验模型

• 批准号: 7681528
• 负责人: Francesco B Ramirez
• 金额: $ 18.65万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7681528
• 关键词: Adult; Affect; Animal Model; Antibodies; Autoimmunity; Blood Vessels; Cell Culture System; Cells; Cessation of life; Clinical; Clinical Management; Clinical Treatment; Collagen; Collagen Gene; Connective Tissue; Connective Tissue Diseases; Dermal; Diagnostic; Disease; Disease Outcome; Disease Progression; Event; Experimental Models; Fibroblasts; Fibrosis; Genetic Transcription; Goals; Hydrogen Peroxide; Immune; Individual; Inflammation; Inflammatory; Knowledge; Lesion; Literature; Mediating; Modeling; Molecular; Morbidity - disease rate; Muscle; Organ; Pathogenesis; Pathway interactions; Patients; Phenotype; Platelet-Derived Growth Factor; Platelet-Derived Growth Factor Receptor; Production; Property; Reactive Oxygen Species; Regulation; Research; Scleroderma; Serum; Severities; Signal Transduction; Skin; Systemic Scleroderma; Therapeutic Intervention; Tissues; Visceral; Woman; base; clinically significant; design; effective therapy; end-stage organ failure; high risk; improved; innovation; mortality; novel; novel therapeutics; prognostic; public health relevance; receptor; receptor expression; stem; tool

DESCRIPTION (provided by applicant): We seek to advance knowledge of the mechanisms responsible for excessive collagen production by scleroderma fibroblasts. Scleroderma (Systemic Sclerosis; SSc) is a clinically heterogeneous and poorly understood disorder of the connective tissue that is characterized by vascular, immune/inflammatory and fibrotic manifestations. In spite of much effort, there are currently neither effective therapies nor reliable diagnostic/prognostic tools to manage the progression of tissue fibrosis, the main cause of morbidity and mortality in SSc. We base this application on exciting new evidence that circulating auto-antibodies against the PDGF receptor (PDGFR) are causally associated with the pro-fibrotic phenotype of SSc fibroblasts. Specifically, we have shown that anti-PDGFR auto-antibodies are only present in SSc sera, and that they can convert healthy fibroblasts into SSc-like cells. Identified markers of fibroblasts activation include excessive reactive oxygen species (ROS) production, Ha-Ras stabilization, increased PDGFR levels, and amplified collagen I transcription through TGF-2 independent activation of Smad3. We hypothesize a disease mechanism whereby anti-PDGFR auto-antibodies trigger a ROS-driven signaling cascade that promotes unopposed production of TGF-2, PDGFR, and collagen. Our model is in line with previous findings of elevated PDGFR in association with deregulated TGF-2 activity in SSc dermal lesions and explanted fibroblasts. It is also consistent with evidence of functional relationships between Ras and Smad signals, and reciprocally positive regulation of PDGF and TGF-2 signals. We propose to characterize key downstream events and pathogenic properties of the anti-PDGFR auto-antibodies. Whereas the former aim will be pursued using traditional cell culture systems, the latter one will employ a novel animal model of skin fibrosis. Completing these studies will improve our understanding of SSc pathogenesis, and may also identify novel therapeutic opportunities to manage tissue fibrosis more effectively. PUBLIC HEALTH RELEVANCE: Scleroderma is a relatively rare and often fatal disorder that affects mostly adult women. Death occurs from end-stage organ failure caused by massive fibrosis in the connective tissue of skin, vessels and internal organs. There are currently neither effective therapies nor reliable prognostic tools to manage disease progression, mostly due to our limited understanding of scleroderma pathogenesis. We have recently discovered that circulating auto-antibodies against PDGFR receptor (PDGFR) may represent a main determinant of the pro-fibrotic phenotype of scleroderma fibroblasts. The present application seeks to further characterize key mechanisms and pathogenic properties of anti-PDGFR auto-antibodies, with the long-term goal of developing new targeted therapies against this devastating disorder.

描述（由申请人提供）：我们试图促进对索硬皮纤维细胞产生过度胶原蛋白产生的机制的了解。硬皮病（全身性硬化症； SSC）是一种临床上异质性且知之甚少的结缔组织疾病，其特征是血管，免疫/炎症和纤维化表现。尽管有很多努力，但目前既没有有效的疗法，也没有可靠的诊断/预后工具来管理组织纤维化的进展，这是SSC发病率和死亡率的主要原因。我们以令人兴奋的新证据为基础，表明针对PDGF受体（PDGFR）循环自身抗体与SSC成纤维细胞的促纤维化表型有关。具体而言，我们已经表明，抗PDGFR自动抗体仅存在于SSC Sera中，并且可以将健康的成纤维细胞转化为SSC样细胞。鉴定出的成纤维细胞激活的标记包括过量的活性氧（ROS）产生，HA-RAS稳定，PDGFR水平升高以及通过TGF-2独立激活SMAD3的胶原I转录。我们假设一种疾病机制，抗PDGFR自动抗体会触发ROS驱动的信号传导级联反应，从而促进TGF-2，PDGFR和胶原蛋白的无反应产生。我们的模型与先前对PDGFR升高的发现以及SSC真皮病变中的TGF-2活性和外植纤维细胞相关的发现。它也与RAS和SMAD信号之间功能关系的证据以及PDGF和TGF-2信号的相互正调节一致。我们建议表征抗PDGFR自动抗体的关键下游事件和致病特性。前者将使用传统的细胞培养系统来追求前一个目标，而后者将采用一种新型的皮肤纤维化动物模型。完成这些研究将提高我们对SSC发病机理的理解，还可以鉴定出更有效地管理组织纤维化的新型治疗机会。 公共卫生相关性：硬皮病是一种相对罕见的，通常影响成年女性的致命疾病。死亡是由于皮肤，血管和内脏的结缔组织中大量纤维化引起的终阶段器官衰竭而发生的。目前既没有有效的疗法，也没有可靠的预后工具来管理疾病进展，这主要是由于我们对硬皮病发病机理的理解有限。我们最近发现，针对PDGFR受体（PDGFR）的循环自身抗体可能代表了硬皮病成纤维细胞促纤维化表型的主要决定因素。本应用程序旨在进一步表征抗PDGFR自动抗体的关键机制和致病特性，其长期目标是开发针对这种毁灭性疾病的新靶向疗法。