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（由申请人提供）：系统性硬化症（SSc）是一种破坏性疾病，没有疾病修饰治疗。纤维化是SSc的标志，是由成纤维细胞活化引起的，具有胶原过度产生和肌成纤维细胞分化。转化生长因子-b（transforminggrowthfactor-b，TGF-b）是一种强有力的成纤维细胞活化诱导剂，在SSc的发病机制中起关键作用。TGF-β反应通过细胞内Smad途径和p300（转录共激活因子和组蛋白乙酰转移酶）介导。最近，我们发现过氧化物酶体增殖物激活受体（过氧化物酶体增殖物激活受体）-3在正常成纤维细胞中表达。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配体废除TGF-β诱导的胶原基因表达，表明PPAR-g的一个重要的新的生物活性。我们还证实了PPAR-g蛋白和mRNA的表达在一些SSc患者中降低。我们假设PPAR-g是纤维化反应的内源性抑制因子，受损的表达或活性可能是SSc进行性纤维化的一个因素;因此PPAR-g可能是抗纤维化治疗的新靶点。我们将从体内外两方面探讨PPAR-g的抗肝纤维化作用及其机制。在具体目标1中，我们将表征PPAR-g在具有缺陷性内源性PPAR-g的小鼠和人细胞中的抗TGF-B作用机制，并检查PPAR-g对TGF-B信号传导的调节。在具体目标2中，我们将研究p300在介导TGF-β反应和与PPAR-g的拮抗性串扰中的作用。在具体目标3中，我们将检查PPAR-g配体在硬皮病小鼠模型中的作用，并研究具有成纤维细胞特异性PPAR-g条件性缺失的新型转基因小鼠中的纤维化反应。在具体目标4中，我们将检查PPAR-g在SSc中的表达、活性和临床相关性。这些研究将加深我们对SSc中异常成纤维细胞活化的理解，并首次深入了解PPAR-g在该过程中的作用。这项研究将加速SSc和其他纤维化疾病的新型抗纤维化治疗的发展。 公共卫生相关性：系统性硬化症是一种罕见疾病，其发病机制知之甚少，也没有改善疾病的治疗方法。抗纤维化治疗可以改善SSc以及其他纤维化疾病的生存率和生活质量。最近的研究表明，PPAR-g是纤维化反应的有效负调节剂，并可能代表新的治疗靶点。目前，对PPAR-g在SSc中的调节和作用一无所知。拟议的研究将提供SSc中纤维化的更好定义，PPAR-g在调节反应中的作用，以及靶向PPAR-g治疗SSc的潜在临床效用。