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

• 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
• 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

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）：全身性硬化症（SSC）是一种毁灭性的渐进多系统纤维化疾病，会影响皮肤和其他器官；目前尚无批准或有效的疗法。该疾病估计有30万美国人，这是高发病和死亡率的主要公共卫生问题。纤维化的过程是多种人类疾病和涉及纤维化的疾病的常见最终途径，导致工业化国家所有死亡的45％。在此提案中，我计划研究脂肪PPAR-GAMMA在纤维化过程中，特别是在SSC动物模型中的作用。因为我们已经观察到皮肤纤维化与皮下脂肪组织丧失有关，并且由于我们实验室的工作表明，PPAR-GAMMA在SSC发病机理中很重要，所以我希望发现脂肪细胞在纤维化中是否起重要作用，以及PPAR-GAMMA如何影响这一点。我首先计划调查功能功能的脂肪细胞PPAR-pPAR-GAMMA是否可以通过施用具有组成式激活的PPAR-GAMMA或PPAR-GAMMA抑制剂的SSC诱导的SSC的皮肤纤维化模型来预防纤维化。然后，我将执行细胞培养实验，以确定PPAR-GAMMA功能如何改变脂肪细胞命运，可溶性因子的产生以及对包括成纤维细胞和巨噬细胞在内的其他重要细胞的脂肪细胞影响。这项工作将有助于确定脂肪与纤维化过程的相关性，并有可能通过将脂肪组织作为SSC纤维化的重要因素来转移范式。这项培训补助金的工作将在John Varga博士的监督下进行，John Varga博士是SSC领域的领先专家之一和纤维化发病机理。除了获得Varga博士的指导之外，由于该项目的多学科性质，我还将拥有具有脂肪生物学和核受体（Barish博士）以及小鼠病理学专业知识的顾问（Tourtellotte博士）。尽管SSC是一种多机器人疾病，但这项工作侧重于皮肤纤维化，因此与NIAMS的任务高度相关，该任务支持研究肌肉骨骼和皮肤病的原因以及对科学家进行此类研究的培训。这个指导的项目既包括正式的教学和研究培训，并将导致我发展PPAR-GAMMA生物学方面的专业知识以及脂肪形成与纤维化之间的关系。这项工作将帮助我发展成为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。 公共卫生相关性：系统性硬化症（SSC）是一种多系统纤维化疾病，具有高发病率和死亡率，没有有效的治疗方法。纤维化是SSC的标志，与脂肪流失始终相关，但脂肪与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途径的见解，目的是更好地了解SSC中的纤维化并利用这种理解来开发SSC和其他纤维化疾病的新型治疗方式。