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

项目总结/摘要 硒蛋白合成受损的医学后果随着研究人员的鉴定而变得明显。 硒代半胱氨酸插入序列结合蛋白2（SBP 2）基因中的第一个突变的PI导致了 SBP 2缺乏综合征SBP 2是Sec掺入和硒蛋白的必需因子 合成.受影响的受试者存在特征性甲状腺检查异常，这些异常在 其他遗传或获得性缺陷，并且尚未通过靶向硒蛋白的动物模型复制 合成.虽然甲状腺表型被认为是由甲状腺功能异常引起的， 硒酶脱碘酶，负责这种一致的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， 表现为生长迟缓、先天性肌病、发育迟缓、不育、青春期延迟、复杂 免疫缺陷和代谢参数与胰岛素敏感性增加。报告的唯一成人患者是 35岁，具有最复杂的表型，表现出列出的大多数不同异常 以上这引起了人们对已知携带隐性SBP 2的年轻患者的可能性的关注。 随着年龄的增长，缺乏可能会出现新的健康问题。由于许多问题已经提出了由 由于缺乏人的SBP 2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。目前的建议解决了这一需要，使用 由PI产生的SBP 2缺陷小鼠模型。为了绕过完整Sbp 2的早期致死性， 缺乏时，采用cre-雌激素受体/loxP方法来工程化诱导的小鼠cR/iCKO。 重要的是，人SBP 2缺陷的表型在Sbp 2缺陷小鼠中复制。与该重要 这项建议旨在开始阐明硒蛋白介导的病理学方面的解剖 特异性甲状腺表型和代谢表现。解剖不同的组成部分 有助于独特的血清甲状腺功能测试，下丘脑-垂体-甲状腺轴的组分 将在基线和挑战性条件下（如外源性甲状腺激素）进行详细研究 局考虑到某些硒蛋白促进肥胖和胰岛素抵抗， 其他人保护它，Sbp 2缺乏症的代谢表型是多器官的结果。 捐款.代谢表型的特征将在Sbp 2缺陷小鼠中通过详细的 在代谢组织中的研究中，将在代谢笼中研究的小鼠中测定代谢参数， 在基线和挑战条件下，当喂食高脂肪饮食时。拟议研究的结果将 显著推进我们对SPB 2在TH稳态和细胞代谢中的作用的理解， 为我们理解硒蛋白生物学的范式转变奠定基础。

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.