Regulation of Thyroid Function by Retinol Saturase

视黄醇饱和酶调节甲状腺功能

• 批准号: 493873521
• 负责人: Professor Dr. Michael Schupp, Ph.D.
• 金额: --
• 依托单位: Institut für Pharmakologie (CCM)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/493873521?language=en
• 关键词: Regulation; Thyroid; Function; Retinol; Saturase

Thyroid hormones are major regulators of growth, cell differentiation, and energy homeostasis. These hormones are synthesized in follicular epithelial cells of the thyroid gland and secreted into the blood. Upon the uptake into tissues, locally expressed deiodinases then fine-tune thyroid hormone action in a cell type-specific manner. We found that the enzyme Retinol Saturase (RetSat), a NAD(P)H or FADH-dependent oxidoreductase initially shown to reduce retinol to 13,14-dihydroretinol that may also catalyze other reactions, is strongly expressed in murine and human thyroid gland. Moreover, RetSat expression in the murine thyroid was altered by iodide feeding, a known modulator of thyroid function. To dissect the function of RetSat in the thyroid, we generated a new genetic mouse model that deletes RetSat specifically in thyrocytes. Preliminary data gained from these mice implicate RetSat in the synthesis of thyroid hormones. Hence, this proposal aims at investigating the underlying mechanisms, characterize the phenotypical consequences, and elucidate RetSat’s role in hypo-and hyperthyroid states. Addressing these question will decipher the function of RetSat in the thyroid gland and may identify a novel pharmacologic target to treat thyroid dysfunction and related metabolic pathologies.

甲状腺激素是生长、细胞分化和能量稳态的主要调节剂。这些激素在甲状腺滤泡上皮细胞中合成并分泌到血液中。在摄取到组织中后，局部表达的脱碘酶然后以细胞类型特异性方式微调甲状腺激素作用。我们发现，视黄醇饱和酶（RetSat）是一种NAD（P）H或FADH依赖性氧化还原酶，最初显示可将视黄醇还原为13，14-二氢视黄醇，也可催化其他反应，在鼠和人甲状腺中强烈表达。此外，RetSat在小鼠甲状腺中的表达被碘喂养改变，碘是一种已知的甲状腺功能调节剂。为了剖析RetSat在甲状腺中的功能，我们生成了一种新的遗传小鼠模型，该模型专门在甲状腺细胞中删除RetSat。从这些小鼠获得的初步数据表明RetSat参与甲状腺激素的合成。因此，该提案旨在研究潜在的机制，表征表型后果，并阐明RetSat在甲状腺功能减退和甲状腺功能亢进状态中的作用。解决这些问题将破译RetSat在甲状腺中的功能，并可能确定一种新的药理学靶点来治疗甲状腺功能障碍和相关的代谢病理学。