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. ? ?
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