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

PPAR-γ 在系统性硬化症异常脂肪生成和纤维化中的作用

基本信息

批准号：
8594837
负责人：
Benjamin Douglas Korman
金额：
$ 6.19万
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：
2013-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8594837
关键词：
Adipocytes Adipose tissue Affect Agonist American Animal Model Animals Biology Bleomycin Cell Culture Techniques Cell Differentiation process Cell Lineage Cells Cessation of life Dermal Developed Countries Disease Fatty acid glycerol esters Fibroblasts Fibrosis Future Genes Genetic Polymorphism Goals Grant In Vitro Inflammatory Knowledge Lead Ligands Mediator of activation protein Mentors Mentorship Mesenchymal Stem Cells Mission Modality Modeling Morbidity - disease rate Mus Musculoskeletal Diseases National Institute of Arthritis and Musculoskeletal and Skin Diseases Nature Nuclear Receptors Organ PPAR gamma Pathogenesis Pathology Pathway interactions Patients Peroxisome Proliferator-Activated Receptors Phenotype Play Process Production Public Health Research Research Personnel Research Support Research Training Resistance Rheumatology Role Scientist Scleroderma Signal Transduction Skin Source Stem cells Supervision Systemic Scleroderma Testing Training Transgenic Mice Work adipokines effective therapy fibrogenesis gain of function gain of function mutation human disease in vivo insight lipid biosynthesis macrophage mortality multidisciplinary novel paracrine prevent public health relevance research study skills skin disorder subcutaneous

项目摘要

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.

描述（由申请人提供）：系统性硬化症（SSc）是一种破坏性的进行性多系统纤维化疾病，影响皮肤和其他器官；目前尚无批准或有效的疗法。该疾病影响了大约 30 万美国人，是一个具有高发病率和死亡率的重大公共卫生问题。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近 45% 的死亡。在本提案中，我计划研究脂肪 PPAR-γ 在纤维化过程中的作用，特别是在 SSc 动物模型中。因为我们观察到皮肤纤维化与皮下脂肪组织损失相关，而且我们实验室的工作已经证明 PPAR-gamma 在 SSc 发病机制中很重要，所以我希望发现脂肪细胞是否在纤维化中发挥重要作用，以及 PPAR-gamma 如何可能在 SSc 发病机制中发挥重要作用。影响这个。我首先计划通过将博来霉素诱导的 SSc 皮肤纤维化模型应用于 PPAR-gamma 持续激活或 PPAR-gamma 阻遏物缺失的转基因小鼠，研究脂肪细胞 PPAR-gamma 功能的获得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（包括成纤维细胞和巨噬细胞）的影响。这项工作将有助于确定脂肪与纤维化过程的相关性，并可能通过暗示脂肪组织是 SSc 纤维化的重要贡献者来改变范式。该培训资助的工作将在 John Varga 博士的监督下进行，John Varga 博士是 SSc 和纤维化发病机制领域的世界领先专家之一。除了 Varga 博士的指导外，由于该项目的多学科性质，我还将拥有在脂肪生物学和核受体（Barish 博士）以及小鼠病理学（Tourtellotte 博士）方面具有专业知识的顾问。虽然 SSc 是一种多器官疾病，但这项工作重点关注真皮纤维化，因此与 NIAMS 的使命高度相关，即支持肌肉骨骼和皮肤疾病病因的研究以及培训科学家进行此类研究。这个指导项目包括正式的教学和研究培训，将引导我发展 PPAR-γ 生物学以及脂肪生成和纤维化之间关系的专业知识。这项工作将帮助我发展成为一名独立研究者所需的知识和技能，并最终成为风湿病学和 SSc 研究领域的未来领导者。公众健康相关性：系统性硬化症（SSc）是一种多系统纤维化疾病，发病率和死亡率很高，并且没有有效的治疗方法。纤维化是 SSc 的标志，并且始终与脂肪减少相关，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，并提供对 PPAR-gamma 途径的深入了解，目的是更好地了解 SSc 中的纤维化，并利用这种了解开发新的方法。 SSc 和其他纤维化疾病的治疗方式。