PPAR-Gamma's Role in Aberrant Adipogenesis and Fibrosis in Systemic Sclerosis

描述(申请人提供)：系统性硬化症(SSC)是一种破坏性的进行性多系统纤维性疾病，影响皮肤和其他器官；目前还没有批准或有效的治疗方法。据估计，这种疾病影响着30万美国人，是一个主要的公共卫生问题，发病率和死亡率都很高。纤维化过程是多种人类疾病的共同最终途径，在工业化国家，涉及纤维化的疾病导致了近45%的死亡。在这项提案中，我计划研究脂肪PPAR-γ在纤维化过程中的作用，特别是在SSC的动物模型中。因为我们已经观察到皮肤纤维化与皮下脂肪组织丢失有关，而且我们实验室的工作已经证明PPAR-γ在SSC的发病机制中起重要作用，我希望发现脂肪细胞在纤维化中是否发挥重要作用，以及PPAR-γ可能如何影响这一点。我首先计划通过将博莱霉素诱导的SSC皮肤纤维化模型应用于具有结构性激活的PPAR-γ或丢失PPAR-伽马抑制物的转基因小鼠，来研究脂肪细胞PPAR-γ功能的增加是否可以预防纤维化。然后，我将进行细胞培养实验，以确定PPAR-γ功能如何改变脂肪细胞的命运，可溶性因子的产生，以及脂肪细胞对其他重要细胞的影响，包括成纤维细胞和巨噬细胞。这项工作将有助于确定脂肪与纤维化过程的相关性，并可能通过将脂肪组织作为SSC纤维化形成的重要贡献者来潜在地转变范式。这项培训赠款中的工作将在约翰·瓦尔加博士的监督下进行，他是SSC和纤维化发病机制方面的世界领先专家之一。除了有瓦尔加博士的指导外，由于这个项目的跨学科性质，我还将有在脂肪生物学和核受体(巴里什博士)以及老鼠病理学(图尔特洛特博士)方面具有专业知识的顾问。虽然SSc是一种多器官疾病，但这项工作侧重于皮肤纤维化，因此与NIAMS支持肌肉骨骼和皮肤病原因研究以及培训科学家进行此类研究的任务高度相关。这个有指导的项目包括正式的教学和研究培训，将引导我发展PPAR-伽马生物学以及脂肪生成和纤维化之间的关系的专业知识。这项工作将帮助我发展必要的知识和技能，成为一名独立的调查员，并最终成为风湿病和SSC研究领域的未来领导者。 公共卫生相关性：系统性硬化症(SSC)是一种发病率和死亡率高的多系统纤维性疾病，目前尚无有效的治疗方法。纤维化是SSC的标志，一直与脂肪减少有关，但脂肪和纤维化之间的关系尚不清楚。通过进行动物和细胞培养研究，这项工作将有助于确定脂肪细胞是否以及如何在纤维化中发挥关键作用，并为PPAR-伽马途径提供见解，以更好地了解SSC的纤维化，并利用这一理解开发SSC和其他纤维化疾病的新治疗模式。

DESCRIPTION (provided by applicant): Systemic sclerosis (SSc) is a devastating progressive multisystem fibrotic disease which affects the skin and other organs; there are currently no approved or effective therapies. The disease affects an estimated 300,000 Americans and is a major public health concern with high morbidity and mortality. The process of fibrosis is a common final pathway for multiple human diseases and diseases involving fibrosis cause nearly 45% of all deaths in industrialized nations. In this proposal, I plan to investigate the role of adipose PPAR-gamma on the process of fibrosis and specifically in animal models of SSc. Because we have observed that skin fibrosis is associated with subcutaneous adipose tissue loss and because work in our lab has demonstrated that PPAR-gamma is important in SSc pathogenesis, I hope to discover whether adipocytes play an important role in fibrosis and how PPAR-gamma may influence this. I first plan to investigate whether adipocyte PPAR-gamma gain of function can prevent fibrosis by applying the bleomycin-induced skin fibrosis model of SSc to transgenic mice with either constitutively activated PPAR-gamma or loss of PPAR-gamma repressors. I will then perform cell culture experiments to determine how PPAR-gamma function may alter adipocyte cell fate, production of soluble factors, and adipocyte effects on other important cells including fibroblasts and macrophages. This work will help determine the relevance of fat to the process of fibrosis and could potentially be paradigm shifting by implicating adipose tissue as an important contributor to fibrogenesis in SSc. The work in this training grant will be performed under the supervision of Dr. John Varga, one of the world's leading experts in SSc and the pathogenesis of fibrosis. In addition to having the mentorship of Dr Varga, because of the multidisciplinary nature of this project, I will have consultants with expertise in adipose biology and nuclear receptors (Dr Barish) as well as in mouse pathology (Dr. Tourtellotte). While SSc is a multiorgan disease, this work focuses on dermal fibrosis and therefore is highly relevant to the NIAMS mission of supporting research into the causes of musculoskeletal and skin disease and the training of scientists to perform such research. This mentored project consists both of formal didactics and research training and will lead me to develop expertise in PPAR-gamma biology and the relationship between adipogenesis and fibrosis. This work will help me to develop the knowledge and skills necessary to become an independent investigator and ultimately a future leader in rheumatology and the field of SSc research. PUBLIC HEALTH RELEVANCE: Systemic sclerosis (SSc) is a multisystem fibrotic disease with high morbidity and mortality and has no effective treatment. Fibrosis is the hallmark of SSc and is consistently associated with fat loss, but the relationship between fat and fibrosis is not yet understood. By performing animal and cell culture studies, this work will help determine whether and how fat cells may play a key role in fibrosis and provide insights into the PPAR-gamma pathway with the goal of better understanding fibrosis in SSc and using this understanding to develop novel treatment modalities for SSc and other fibrotic diseases.