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: 6525066
• 负责人: REBECCA S BAHN
• 金额: $ 39.3万
• 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/6525066
• 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：格雷夫斯眼病（GO）是一种自身免疫性眼病， 与格雷夫斯的甲状腺功能亢进症有关有令人信服的实验 有证据表明，眼眶成纤维细胞（包括前脂肪细胞成纤维细胞） 亚群）是GO中的靶细胞。然而，针对其的自身抗原 免疫反应的方向是未知的。促甲状腺激素受体（TSHr）是 是眼眶自身抗原的主要候选者，因为它的参与 有助于解释GO与 甲状腺机能亢进 在最近的研究中，PI已经证实了TSHr mRNA和蛋白的存在， 在GO患者的眼眶脂肪/结缔组织中， 在正常眼眶组织中表达不明显。此外，她还展示了 眼眶前脂肪细胞成纤维细胞，缺乏功能性促甲状腺激素受体的细胞， 在体外分化成成熟的携带TSH r的脂肪细胞。这些和其他 研究结果导致假设：1）GO眼眶中TSHr的表达是 与眼眶前脂肪细胞成纤维细胞中脂肪形成的诱导有关， 2）脂肪细胞TSHr是由 GO中的眼眶浸润淋巴细胞。PI计划检查这些 假设使用我们的系统培养的眼眶前脂肪细胞成纤维细胞 来自GO患者。在具体目标I中，她将定义 成纤维细胞样细胞存在于GO的眼眶中，并确定 调节这些细胞中的脂肪形成。Aim II中的实验旨在 描述TSHr的特征，并阐明TSHr表达与 和脂肪形成。在Aim III中，她将决定是否克隆 来自GO患者的眼眶浸润淋巴细胞识别TSHr，或其他 由自体抗原呈递细胞“天然”加工的抗原。 该研究项目的主要目标是增加对 在GO中的眼眶免疫应答，以使新的和更特异性的治疗 并可能制定针对这种情况的预防策略。