Fibroblast TGF-beta/Signaling in Scleroderma: Modulation by PPAR-gamma

硬皮病中的成纤维细胞 TGF-β/信号转导：PPAR-gamma 的调节

• 批准号: 7814218
• 负责人: John Varga
• 金额: $ 45.75万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-24 至 2011-09-23
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7814218
• 关键词: Biological; Cells; Clinical; Collagen; Collagen Gene; Development; Disease; EP300 gene; Fibroblasts; Fibrosis; Gene Expression; Human; In Vitro; Inflammation; Ligands; Mediating; Messenger RNA; Mus; Myofibroblast; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Orphan Disease; PPAR gamma; Pathogenesis; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Play; Process; Proteins; Quality of life; Regulation; Research; Role; Scleroderma; Signal Transduction; Systemic Scleroderma; Time; Transcription Coactivator; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Mice; Transgenic Model; Up-Regulation; Work; histone acetyltransferase; improved; in vivo; inhibitor/antagonist; insight; insulin sensitivity; lipid biosynthesis; mouse model; novel; novel therapeutics; parent grant; public health relevance; research study; response

DESCRIPTION (provided by applicant): Systemic sclerosis (SSc) is a devastating condition with no disease-modifying treatment. Fibrosis, the hallmark of SSc, is caused by fibroblast activation with collagen overproduction and myofibroblast differentiation. Transforming growth factor-b (TGF-b) is a potent inducer of fibroblast activation, and plays a key role in the pathogenesis of SSc. TGF-b responses are mediated through intracellular Smad pathways and p300, a transcriptional coactivator and histone acetyltransferase. Recently, we found that peroxisome proliferator-activated receptor (PPAR)-3 is expressed in normal fibroblasts. PPAR-g is a nuclear receptor with key roles in adipogenesis and insulin sensitivity. Ligands for PPAR-g are in clinical use to treat type 2 diabetes. We showed that PPAR-g ligands abrogated collagen gene expression induced by TGF-b, indicating an important novel biological activity of PPAR-g. We also demonstrated that expression of PPAR-g protein and mRNA was reduced in some patients with SSc. We hypothesize that PPAR-g is an endogenous suppressor of fibrotic responses, and impaired expression or activity could be a factor in progressive fibrosis in SSc; thus PPAR-g may be a novel target for anti-fibrotic therapy. We will explore the anti-fibrotic role of PPAR-g and its mechanism in vitro and in vivo. In Specific Aim 1, we will characterize the anti-TGF-b mechanisms of action of PPAR-g in mouse and human cells with defective endogenous PPAR-g, and examine the modulation of TGF-b signaling by PPAR-g. In Specific Aim 2 we will examine the role of p300 in mediating TGF-b responses and in the antagonistic cross-talk with PPAR-g. In Specific Aim 3 we will examine the effect of PPAR-g ligands in mouse models of scleroderma, and study the fibrotic response in a novel transgenic mouse with fibroblast-specific conditional deletion of PPAR-g. In Specific Aim 4, we will examine the expression, activity and clinical correlates of PPAR-g in SSc. These studies will deepen our understanding of aberrant fibroblast activation in SSc, and provide the first insight into the role of PPAR-g in the process. The proposed research will accelerate the development of novel anti-fibrotic treatments for SSc and other fibrosing diseases. PUBLIC HEALTH RELEVANCE: Systemic sclerosis is an orphan disease with poorly understood pathogenesis and no disease-modifying treatment. Anti-fibrotic therapy could improve survival and quality of life in SSc as well as other fibrosing conditions. Recent studies indicate that PPAR-g is a potent negative regulator of fibrotic responses and may represent a novel target for therapy. Currently, nothing is known regarding the regulation and role of PPAR-g in SSc. The proposed studies will provide a better definition of fibrosis in SSc, the role of PPAR-g in regulating the response, and the potential clinical utility of therapies targeting PPAR-g in SSc.

描述(申请人提供)：系统性硬化症(SSC)是一种破坏性的疾病，没有改善疾病的治疗方法。纤维化是SSC的标志，是由成纤维细胞活化、胶原过度生成和肌成纤维细胞分化引起的。转化生长因子-b是一种强有力的成纤维细胞激活诱导剂，在系统性硬化症的发病机制中起着关键作用。转化生长因子-b的反应是通过细胞内的Smad通路和p300，一种转录辅助激活因子和组蛋白乙酰转移酶来介导的。最近，我们发现PPAR-3在正常成纤维细胞中有表达。PPAR-g是一种核受体，在脂肪形成和胰岛素敏感性中起关键作用。PPAR-g的配体在临床上用于治疗2型糖尿病。我们发现PPAR-g配体可抑制转化生长因子-b诱导的胶原基因表达，表明PPAR-g具有重要的新生物活性。我们还发现一些SSc患者PPAR-g蛋白和mRNA的表达降低。我们假设PPAR-g是纤维化反应的内源性抑制因子，表达或活性受损可能是SSC进行性纤维化的一个因素；因此，PPAR-g可能成为抗纤维化治疗的新靶点。我们将在体内外探讨PPAR-g的抗纤维化作用及其机制。在特定的目标1中，我们将研究PPAR-g在内源性PPAR-g缺陷的小鼠和人细胞中抗转化生长因子-b的作用机制，并检测PPAR-g对转化生长因子-b信号的调节作用。在特定的目标2中，我们将研究p300在介导转化生长因子-b反应中的作用以及在与PPAR-g的拮抗性串扰中的作用。在特定的目标3中，我们将检验PPAR-g配体在硬皮病小鼠模型中的作用，并研究一种新型的成纤维细胞特异性条件缺失PPAR-g转基因小鼠的纤维化反应。在特定的目标4中，我们将检测PPAR-g在SSC中的表达、活性及其临床相关性。这些研究将加深我们对SSC中成纤维细胞异常激活的理解，并为PPAR-g在这一过程中的作用提供第一个洞察力。这项拟议的研究将加速开发针对SSC和其他纤维化疾病的新型抗纤维化治疗方法。 公共卫生相关性：系统性硬化症是一种孤儿疾病，发病机制知之甚少，也没有治疗疾病的方法。抗纤维化治疗可改善SSC及其他纤维化疾病患者的生存和生活质量。最近的研究表明，PPAR-g是一种有效的纤维化反应的负性调节因子，可能是一个新的治疗靶点。目前，关于PPAR-g在SSC中的调控和作用尚不清楚。建议的研究将为SSC的纤维化提供更好的定义，PPAR-g在调节反应中的作用，以及针对PPAR-g的治疗在SSC中的潜在临床应用。