Cellular location, differential regulation and function of selenoproteins in the human thryoid

正常人甲状腺通过H2O2依赖性过氧化物酶催化的自由基反应产生含碘甲状腺激素，具有非常高的硒含量并表达几种含硒半胱氨酸的蛋白质。严重的硒和碘缺乏导致地方性克汀病，是甲状腺癌演变的危险因素。本项目的第一个目标是表征分泌型硒蛋白P（SeP）在甲状腺组织和甲状腺细胞系中的表达和调节。进一步的研究将解决的问题是否SeP和细胞外谷胱甘肽过氧化物酶同工酶（pGPx）参与局部抗氧化防御反应，并分泌到胶体空间或整个基底外侧膜的顶端甲状腺细胞极。通过原位杂交和免疫组织化学分析甲状腺细胞、基质细胞或血管细胞中硒蛋白的表达。在甲状腺细胞中，硒依赖性分子靶点和功能终点将被确定为氧化还原敏感性转录因子AP 1的氧化激活，AP 1控制增殖并参与细胞转化。甲状腺细胞和单核细胞衍生的细胞之间的相互作用将在硒缺乏和过氧化应激条件下进行研究。我们期待硒蛋白在甲状腺肿，癌症和甲状腺自身免疫性疾病的演变机制和参与的信息。

The normal human thyroid produces iodine-containing thyroid hormones by an H2O2-dependent peroxidase-catalyzed radicalic reaction, has a very high selenium content and expresses several selenocysteine-containing proteins. Severe selenium and iodine deficiencies lead to endemic cretinism and are risk factors for evolution of thyroid cancer. The first goal of this project is to characterize the expression and regulation of the secreted selenoprotein P (SeP) in thyroid tissue and thyroid cell lines. Further studies will address the issue whether SeP and the extracellular glutathione peroxidase isoenzyme (pGPx) participate in local antioxidative defense reactions and are secreted across the apical thyrocyte pole into the colloid space or across the basolateral membrane. Expression of selenoproteins in thyrocytes, stromal or vascular cells will be analyzed by in situ hybridization and immunohistochemistry. In thyrocytes, selenium-dependent molecular targets and functional endpoints will be identified for oxidative activation of the redox-sensitive transcription factor AP1, which controls proliferation and is involved in cell transformation. Interactions between thyrocytes and monocyte-derived cells will be studied under selenium deficiency and peroxidative stress conditions. We expect information on mechanisms and participation of selenoproteins in the evolution of goiter, cancer and thyroid autoimmune disease.