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

描述（由申请人提供）：甲状腺相关眼病（TAO，也称为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，并含有促炎细胞因子和胡萝卜素。TAO的一个标志是眼眶脂肪增加，将眼睛推出眼眶（眼球突出）。TAO是毁容，并可能导致失明。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的一个重要但研究较少的方面。脂肪细胞分化被认为主要由称为过氧化物酶体增殖物激活受体γ（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PPARgamma，天然（15 d-PGJ 2）和合成（例如胰岛素增敏药物罗格列酮）PPARgamma配体均诱导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表明，格雷夫斯患者的循环T淋巴细胞高度表达产生胰高血糖素的酶环氧合酶-2（考克斯-2），并产生PPARgamma配体15 d-PGJ 2。此外，Graves' T细胞将表达PPARgamma的TAO成纤维细胞的子集驱动至脂肪细胞。这些令人兴奋的数据首次证明人类T细胞产生功能性PPARgamma配体，并支持眼眶炎症过程驱动脂肪生成。我们将检验的总体假设是，Graves' T淋巴细胞产生一种PPARgamma配体，该配体诱导表达PPARgamma的眼眶成纤维细胞分化为脂肪细胞。为了检验总体假设，将回答以下三个作为具体目标提出的问题。目标1：格雷夫斯病人T淋巴细胞是否具有高度表达考克斯-2并产生作为PPARgamma配体的胰高血糖素（例如15 d-PGJ 2）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前脂肪形成转录因子PPARgamma？目标3：Thy 1+和Thy 1- Graves眼眶成纤维细胞之间的差异是什么，决定了为什么只有ThyT成纤维细胞分化为脂肪细胞？这些研究将有助于描述炎症细胞和刺激眼眶成纤维细胞分化为脂肪细胞的途径。这一新的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很重要。

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.