Pathways to Fibrosis

描述(由申请人提供)： 摘要在美国，肺纤维化每年影响20万患者。特发性肺纤维化(IPF)是一种严重的肺纤维化，除肺移植外，尚无有效的治疗方法。IPF的发病机制尚不清楚，但细胞因子TGF2上调，可能是重要的。TGF2促进肌成纤维细胞和细胞外基质(ECM)的积聚。过氧化体增殖物激活受体γ(PPAR3)是一种受体和转录因子，调节脂肪生成和胰岛素增敏。现在人们认识到，它也是炎症的下行调节因子。我们的新数据，以及其他人的数据，已经确认PPAR3是一种纤维化形成的衰减剂。具体地说，由PPAR3配体(内源性或人工合成)激活的PPAR3在体外抑制了TGF2介导的关键的促纤维化活性(肌成纤维细胞和ECM积聚)，在体内抑制了肺纤维化。组织谷氨酰胺转氨酶2(TG2)是一种使胶原和纤维连接蛋白等基质分子交联并稳定的酶。过高的TG2活性可能会过度交联基质蛋白。我们新的初步数据表明，TG2在纤维化肺疾病中表达增加，TGF2上调成纤维细胞中TG2的表达，而PPAR3激活抑制TG2的表达。有待检验的总体假设是，IPF中PPAR3的缺乏或失调导致TGF2介导的下游生物活性失控，包括肌成纤维细胞分化、细胞外基质过度产生和TG2上调。目的1.确定轻、中、重度IPF患者组织中是否存在PPAR3蛋白表达的细胞类型特异性缺陷或失调，和/或PPAR3 1/2亚型比值的改变。目的2.评估IPF患者肺组织中TG2活性是否上调，是否导致基质过度交联，以及这是否与PPAR3缺乏有关(在目标1中确定)。这些发现将揭示IPF发病机制的新见解，并可能确定新的治疗靶点。翻译潜力很高，因为几个PPAR3配体现在被FDA批准用于人类治疗糖尿病，并正在接受癌症治疗的评估。(摘要结束) 公共卫生相关性： 肺纤维化(疤痕形成)是一种严重的疾病，几乎没有有效的治疗方法。在这项提案中，我们将确定对控制疾病很重要的新途径，以及哪些途径可以作为未来治疗的目标。我们认为，一种名为过氧化体增殖物激活受体伽马的保护性蛋白在肺纤维化患者中缺乏，导致硬性瘢痕组织沉积增加。

DESCRIPTION (provided by applicant): Abstract Pulmonary fibrosis affects 200,000 patients per year in the USA. Idiopathic pulmonary fibrosis (IPF) is a severe form of pulmonary fibrosis for which there are no effective therapies except lung transplantation. The pathogenesis of IPF is poorly understood, but the cytokine TGF2 is upregulated and likely important. TGF2 drives both myofibroblast and extracellular matrix (ECM) accumulation. Peroxisome proliferator activated receptor gamma (PPAR3) is a receptor and transcription factor that regulates adipogenesis and insulin sensitization. It is now appreciated that it is also a down regulator of inflammation. Our new data, as well as that of others, has identified PPAR3 as an attenuator of fibrogenesis. Specifically, PPAR3 activation by PPAR3 ligands (endogenous or synthetic) inhibits key TGF2-mediated profibrogenic activities (myofibroblast and ECM accumulation) in vitro and pulmonary fibrosis in vivo. Tissue transglutaminase 2 (TG2) is an enzyme that cross-links and stabilizes matrix molecules such as collagen and fibronectin. Excess TG2 activity could excessively cross-link matrix proteins. Our new preliminary data demonstrate that TG2 expression is increased in fibrotic lung disease and that TGF2 up-regulates TG2 in fibroblasts, while PPAR3 activation suppresses TG2 expression. The overall hypothesis to be tested is that deficiency or dysregulation of PPAR3 in IPF leads to uncontrolled TGF2-mediated downstream bioactivities that include myofibroblast differentiation, excess extracellular matrix production and TG2 upregulation. Two specific aims are proposed to test this hypothesis: Aim 1. Determine whether there is cell type specific deficiency or dysregulation of PPAR3 protein expression, and/or alterations in the ratio of PPAR3 1 and 2 isoforms in tissues from patients with mild, moderate or severe IPF compared to controls. Aim 2. Evaluate if there is up-regulation of TG2 activity in lung tissues from patients with IPF resulting in excessive cross-linking of matrix, and whether this is related to PPAR3 deficiency (determined in Aim 1). These findings will reveal new insights into the pathogenesis of IPF and may identify new targets for therapy. The translational potential is high as several PPAR3 ligands are now FDA approved for human use in diabetes and are being evaluated for therapy of cancer. (End of Abstract) PUBLIC HEALTH RELEVANCE: Relevance Pulmonary fibrosis (scarring) is a severe disease with few effective therapies. In this proposal we will identify new pathways which are important in controlling the disease and which can be targeted for future therapy. We propose that a protective protein called the peroxisome proliferator activated receptor gamma is deficient in subjects with lung fibrosis, leading to increased deposition of stiff scar tissue.