Role of T cells and PPARgamma in Graves' orbital fibroblast adipogenesis

描述(申请人提供)：甲状腺相关眼病(TAO，又称Graves‘眼病)是一种严重的自身免疫性疾病，涉及眼眶组织炎症。眼眶组织主要由T淋巴细胞浸润，含有促炎症细胞因子和前列腺素。TAO的一个特征是眼眶脂肪增加，将眼睛推出眼眶(眼球突出)。道是毁容的，可能会导致失明。前脂肪细胞眼眶成纤维细胞是这一过程中的关键效应细胞。眼眶炎症被认为是促使它们分化为脂肪细胞的原因。诱导这种分化的炎症信号仍然是TAO的一个重要方面，但研究较少。脂肪细胞的分化被认为主要由一种名为过氧化物酶体增殖物激活受体伽马(PPARGamma)的转录因子控制。我们的研究表明，人眼眶成纤维细胞高度表达PPARγ，天然的(15d-PGJ2)和合成的(如胰岛素增敏药物罗格列酮)PPARγ配体均可诱导Graves眼眶成纤维细胞亚群分化为脂肪细胞。我们令人信服的新数据显示，Graves病患者的循环T淋巴细胞高度表达前列腺素生成酶环氧合酶-2(COX-2)，并产生PPAR-γ配体15d-PGJ2。此外，Graves的T细胞驱动表达PPARGamma的TAO成纤维细胞的一部分转化为脂肪细胞。这些令人兴奋的数据首次证明了人类T细胞产生了功能性的PPARγ配体，并支持眼眶炎症过程推动脂肪生成。我们将检验的总体假设是，Graves的T淋巴细胞产生一种PPARGamma配体，该配体诱导表达PPARGamma的眼眶成纤维细胞亚群分化为脂肪细胞。以下三个作为具体目标的问题将被回答，以检验总体假设。目的1：Graves病患者的T淋巴细胞是否具有高表达COX-2和产生前列腺素(如15d-PGJ2)作为PPAR-γ配体的独特能力？目的2：Graves眼眶成纤维细胞分化为脂肪细胞的能力是否依赖于促成脂转录因子PPARGamma？目的3：Thy1+和Thy1-Graves眼眶成纤维细胞在决定为什么只有ThyT成纤维细胞分化为脂肪细胞方面有什么不同？这些研究将有助于描绘刺激眼眶成纤维细胞向脂肪细胞分化的炎性细胞和途径。这一新信息将允许开发新的方法来控制炎症和眼眶成纤维细胞的病理分化，这对TAO和其他涉及脂肪沉积的疾病非常重要。

DESCRIPTION (provided by applicant): Thyroid associated ophthalmopathy (TAO, also called Graves' ophthalmopathy) is a serious autoimmune disease involving orbital tissue inflammation. Orbital tissue is infiltrated mainly by T lymphocytes and contains proinflammatory cytokines and prostaglandins. A hallmark of TAO is an increase in orbital fat that pushes the eye out of the orbit (proptosis). TAO is disfiguring and may lead to blindness. Pre-adipocyte orbital fibroblasts are key effector cells in this process. Orbital inflammation is postulated to drive their differentiation to fat cells called adipocytes. The inflammatory signals that induce this differentiation remain an important, yet poorly studied aspect of TAO. Adipocytic differentiation is believed to be mainly controlled by a transcription factor called peroxisome proliferator activated receptor gamma (PPARgamma). Our research shows that human orbital fibroblasts highly express PPARgamma and that both natural (15d-PGJ2) and synthetic (e.g. the insulin-sensitizing drugs rosiglitazone) PPARgamma ligands induce a subset of Graves' orbital fibroblasts to differentiate to adipocytes. Our compelling new data show that circulating T lymphocytes from Graves' patients' highly express the prostaglandin-generating enzyme cycloxygenase-2 (Cox-2) and produce the PPARgamma ligand 15d-PGJ2. Moreover, Graves' T cells drive a subset of PPARgamma expressing TAO fibroblasts to adipocytes. These exciting data are the first to demonstrate that human T cells produce a functional PPARgamma ligand and supports that the process of orbital inflammation drives adipogenesis. The overall hypothesis we will test is that Graves' T lymphocytes produce a PPARgamma ligand that induces a subset of PPARgamma expressing orbital fibroblasts to differentiate to adipocytes. The following three questions posed as specific aims will be answered to test the overall hypothesis. Aim 1: Are Graves' disease human T lymphocytes unique in their ability to highly express Cox-2 and produce prostaglandins (e.g. 15d-PGJ2) that act as PPARgamma ligands? Aim 2: Is the ability of Graves' orbital fibroblasts to differentiate to adipocytes dependent on the pro-adipogenic transcription factor PPARgamma? Aim 3: What are the differences between Thy1+ and Thy1- Graves' orbital fibroblasts that determine why only ThyT fibroblasts differentiate to adipocytes? These studies will help delineate the inflammatory cells and pathways that incite orbital fibroblast differentiation to adipocytes. This new information will permit the development of new approaches to control inflammation and the pathologic differentiation of orbital fibroblasts important for TAO and other diseases that involve fat deposition.