EYE IN GRAVES DISEASE--ROLE OF ORBITAL FIBROBLASTS

格雷夫斯病中的眼睛——眼眶成纤维细胞的作用

• 批准号: 2907078
• 负责人: REBECCA S BAHN
• 金额: $ 38.77万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-01 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2907078
• 关键词: Graves disease; RNase protection assay; adipocytes; antigen presenting cell; autoantigens; autoimmunity; cell differentiation; cellular immunity; cellular pathology; clinical research; cytokine; fibroblasts; flow cytometry; growth factor; hormone receptor; human tissue; immunocytochemistry; lipoprotein lipase; molecular shape; northern blottings; receptor binding; receptor expression; thyrotropin; western blottings

DESCRIPTION: Graves' ophthalmopathy (GO) is an autoimmune eye disorder closed associated with Graves' hyperthyroidsim. There is convincing experimental evidence that the orbital fibroblast (including the preadipocyte fibroblast subpopulation) is the target cell in GO. However, the autoantigen against which the immune response is directed is unknown. The thyrotropin receptor (TSHr) is a prime candidate to be the orbital autoantigen because its involvement would help to explain the close clinical and laboratory associations between GO and hyperthyroidism. In recent studies, the PI has demonstrated the present of TSHr mRNA and protein in orbital adipose/connective tissues from patients with GO, wile TSHr expression was not apparent in normal orbital tissues. In addition, she showed that orbital preadipocyte fibroblasts, cells lacking fucntional TSHr, can be differentiated in vitro into mature TSHr-bearing adipocytes. These and other findings led to hypothesize that: 1)expression of TSHr in the orbit in GO is linked to the induction of adipogenesis in orbital preadipocyte fibroblasts, and that; 2) the adipocyte TSHr is the orbital autoantigen recognized by orbital-infiltrating lymphocytes in GO. The PI plans to examine these hypotheses using our system of cultured orbital preadipocyte fibroblasts derived from pateints with GO. In specific aim I, she will define the fibroblast-like cells present in the orbit in GO and identify factors that modulate adipogenesis in these cells. Experiments in Aim II are designed to characterize the obital TSHr and to clarify the link between TSHr expression and adipogenesis in the orbi. In Aim III, she will determine whether cloned orbital-infiltrating lymphocytes from patients with GO recognize TSHr, or other antigens that are processed "naturally" by autologous antigen-presenting cells. The main goal of the research program is to increase understanding of the orbital immune response in GO in order that novel and more specific therapeutic and preventive strategies for this condition might be developed.

描述：Graves眼病(GO)是一种自身免疫性闭合性眼病 与格雷夫斯甲亢有关。有令人信服的实验 眼眶成纤维细胞(包括前脂肪细胞成纤维细胞) 子群体)是围棋中的目标细胞。然而，与之对抗的自身抗原 免疫反应的导向尚不清楚。促甲状腺激素受体(TSHR)是 作为轨道自身抗原的主要候选者，因为它的参与将 帮助解释GO和GO之间密切的临床和实验室联系 甲亢。 在最近的研究中，PI证明了TSHR基因和蛋白的存在 GO、TSHR患者眼眶脂肪/结缔组织中的变化 在正常眼眶组织中表达不明显。此外，她还展示了 缺乏功能性TSHR的眼眶前脂肪细胞成纤维细胞可以 体外分化为成熟的含TSHR的脂肪细胞。这些和其他 结果提示：1)GO眼眶组织中TSHR的表达 与诱导眼眶前脂肪细胞成纤维细胞成脂有关， 2)脂肪细胞TSHR是人类识别的眼眶自身抗原 GO的眶内浸润性淋巴细胞。私家侦探计划检查这些 利用我们的眼眶前脂肪细胞成纤维细胞培养系统的假说 从围棋的派生而来。在具体的目标一中，她将定义 成纤维细胞样细胞存在于GO的眼眶中并鉴定 调节这些细胞的脂肪生成。AIM II的实验旨在 描述外伤性TSHR的特征并阐明TSHR表达之间的联系 和眼眶内的脂肪生成。在AIM III中，她将决定是否克隆 GO患者的眼眶浸润性淋巴细胞识别TSHR或其他 由自体抗原提呈细胞“自然”处理的抗原。 研究计划的主要目标是增加对 围棋眼眶免疫反应新的、更特异的治疗 并可能针对这种情况制定预防策略。