Mouse Sbp2 deficiency models the multi-system syndrome of human SBP2 defects

项目摘要/摘要 硒蛋白合成受损的医学后果随着对 硒半胱氨酸插入序列结合蛋白2(SBP2)基因第一次突变引起的 SBP2缺乏证。SBP2是SEC掺入和硒蛋白所必需的因子 综合。受影响的受试者会出现特征性的甲状腺测试异常，这些异常在 其他遗传性或获得性缺陷，尚未被靶向硒蛋白的动物模型复制 综合。虽然甲状腺表型被认为是由于甲状腺功能异常引起的 对于硒脱碘酶，导致这种一致模式的确切机制仍然难以捉摸。 这种综合征缺陷的其他表型成分也反映了多种硒蛋白缺乏， 表现为生长发育迟缓、先天性肌病、发育迟缓、不孕、青春期延迟、复合体 胰岛素敏感性增加的免疫缺陷和代谢参数。唯一报告的成年患者是 35岁，具有最复杂的表型，表现出列出的大多数不同的异常 上面。这引起了人们对已知患有隐性SBP2的年轻患者的担忧 随着年龄的增长，缺乏症可能会出现新的健康问题。由于已经提出了许多问题， 人类SBP2缺乏症的表型，需要在模型生物体中进行体内研究，以充分评估 导致这种多效性表型的病理生理学。当前的提案解决了这一需求，使用了 小鼠脾虚所致SBP2虚证模型。绕过完整的Sbp2的早期致命性 利用雌激素受体/loxP基因工程方法诱导小鼠Null/iCKO。 重要的是，人类SBP2缺乏症的表型在Sbp2缺陷症小鼠中复制。在这一关键时刻 手中的工具这项提案旨在通过解剖开始阐明硒蛋白介导的病理学的各个方面 病原性甲状腺表型和代谢表现。剖析不同的组成部分 有助于独特的血清甲状腺功能测试，下丘脑-垂体-甲状腺轴的成分 将在基线和挑战性条件下进行详细调查，例如外源性甲状腺激素 行政管理。考虑到某些硒蛋白可以促进肥胖和胰岛素抵抗，而 Sbp2缺乏症的代谢表型是多器官共同作用的结果。 贡献。Sbp2基因缺陷小鼠的代谢表型特征将通过详细的 在代谢组织的研究中，代谢参数将在代谢笼中被研究的小鼠中确定，在 在高脂肪饮食的基础上和具有挑战性的条件下。建议的研究结果将会 极大地促进了我们对SPB2在体内平衡和细胞代谢中的作用的理解，以及 为我们理解硒蛋白生物学的范式转变奠定了基础。

PROJECT SUMMARY/ABSTRACT The medical consequences of impaired selenoprotein synthesis became apparent with the identification by the PI of the first mutations in the selenocysteine insertion sequence binding protein 2 (SBP2) gene causing a syndrome of SBP2 deficiency. SBP2 is an essential factor required for the Sec incorporation and selenoprotein synthesis. Affected subjects present characteristic thyroid tests abnormalities that have not been identified in other inherited or acquired defects and have not been replicated by animal models targeting selenoprotein synthesis. Although the thyroid phenotype is presumed to be caused by abnormal function of the selenoenzymes deiodinases, the exact mechanisms responsible for this consistent pattern remain elusive. Other phenotypic components of this syndromic defect also reflect multiple selenoprotein deficiencies, manifested with growth delay, congenital myopathy, developmental delay, infertility, delayed puberty, complex immune deficits and metabolic parameters with increased insulin sensitivity. The only adult patient reported is 35 years old and has the most complex phenotype, manifesting most of the different abnormalities listed above. This raises concern for the possibility that the young patients known to harbor recessive SBP2 deficiency might manifest new health problems as they age. As many questions have been raised by the human phenotype of SBP2 deficiency, in-vivo studies in a model organism are required to fully assess the pathophysiology responsible for this pleiotropic phenotype. The current proposal addresses this need, using a mouse model of SBP2 deficiency generated by the PI. To bypass the early lethality of complete Sbp2 deficiency, a cre-estrogen receptor/loxP approach was employed to engineer induced mice Null/iCKO. Importantly, phenotypes of human SBP2 deficiency were replicated in the Sbp2 deficient mice. With this critical tool in hand this proposal aims to begin elucidate aspects of selenoprotein-mediated pathology by dissecting the pathognomonic thyroid phenotypes and the metabolic manifestations. To dissect the different components contributing to the unique serum thyroid function tests, components of the hypothalamic-pituitary-thyroid axis will be investigated in detail at baseline and in challenging conditions, such as exogenous thyroid hormone administration. Considering that certain selenoproteins act to promote adiposity and insulin resistance whereas others protect against it, the resulting metabolic phenotype of Sbp2 deficiency is the result of multi-organ contributions. Features of the metabolic phenotype will be investigated in Sbp2 deficient mice through detailed studies in metabolic tissues, metabolic parameters will be determined in mice studied in metabolic cages, at baseline and in challenging conditions when fed high fat diet. The results of the proposed studies will significantly advance our understanding of the role of SPB2 in TH homeostasis and cellular metabolism, and lay the groundwork for a paradigm shift in our understanding of selenoprotein biology.