Adiponectin: Effects on Graves' Ophthalmopathy

描述（由申请人提供）： 许多不同的疾病状态，包括格雷夫斯病，与眶后脂肪组织的过度增殖有关。 虽然我们对格雷夫斯病的根本原因有了很好的了解，但我们未能解释疾病进展期间观察到的一些病理生理变化，例如由于眶后脂肪组织过度增生而导致的格雷夫斯相关的外眼症。 过去，由于缺乏适当的小鼠模型来充分模拟这种疾病的特定方面，确定这种脂肪增生的分子机制的进展受到阻碍。 我们最近建立了一种新的小鼠模型，首次显示眶后脂肪组织的变化，使人联想到某些患者中与Graves病相关的病理生理变化。 暴露于长期升高的血清水平的脂肪细胞特异性分泌蛋白脂联素通过转基因过表达导致大量增生的眶后脂肪垫。 与脂联素在Graves病相关的眶后增生中的可能作用一致，Graves病患者的血清脂联素水平升高。 我们建议确定脂联素的贡献，这种增生。 我们的工作假设表明，脂联素水平的长期升高与其他与Graves病相关的激素变化相关，导致该脂肪组织的选择性过度增殖。 我们希望：I）进一步表征该转基因小鼠系作为格雷夫斯相关外突眼症的潜在模型系统，并探索导致眶后脂肪增生过早或延迟发作的可能的激素操纵。II）通过使用PPAR拮抗剂或激动剂来测试药理学干预以建立治疗模式。III）在脂肪增生特别突出的Graves患者亚组中，建立血清脂联素增加与眶后脂肪增生之间更可靠的相关性。 结合起来，这些实验将确定已被证明对全身胰岛素敏感性有积极影响的新型激素脂联素是否也可能在慢性高水平下导致Graves病过程中选择性脂肪垫的增生。

DESCRIPTION (provided by applicant): A number of different disease states, including Graves' disease, are associated with hyperproliferation of the retro-orbital adipose tissue. While we have a good understanding of the underlying causes for Graves' disease, we fail to explain some of the pathophysiological changes observed during disease progression, such as the Graves'-associated exopthalmos due to hyperproliferation of the retro-orbital adipose tissue. Progress towards identifying a molecular mechanism for this adipose hyperplasia has been hampered in the past by the lack of an appropriate mouse model that adequately mimics this particular aspect of the disease. We have recently established a novel mouse model that for the first time displays changes in retro-orbital adipose tissue reminiscent of the pathophysiologic changes associated with Graves' disease in some patients. Exposure to chronically elevated serum levels of the adipocyte-specific secretory protein adiponectin through transgenic overexpression results in massive hyperplasia of the retro-orbital fat pad. In agreement with a possible role of adiponectin in the Graves' disease associated retro-orbital hyperplasia, serum adiponectin levels are elevated in a subset of Graves' patients. We propose to define the contribution of adiponectin to this hyperplasia. Our working hypothesis states that chronically elevated levels of adiponectin in association with other hormonal changes connected with Graves' disease leads to the selective hyperproliferation of this adipose tissue. We would like to: I) Further characterize this transgenic mouse line as a potential model system for Graves'-associated exophtalmos and explore possible hormonal manipulations that lead to premature or delayed onset of retro-orbital fat hyperplasia. II) Test pharmacological interventions through use of PPAR antagonists or agonists to establish a treatment modality. III) Establish a firmer correlation between increased serum adiponectin and retroorbital adipose hyperplasia in the subset of Graves patients in which adipose hyperplasia is particularly prominent. Combined, these experiments will establish whether the novel hormone adiponectin that has been shown to positively affect systemic insulin sensitivity, may at chronically high levels also be responsible for the hyperplasia of selective adipose pads in the course of Graves' disease.