THYROID PHYSIOLOGY STUDIES OF INHERITED DISORDERS

描述：（改编自申请人的摘要）。其广泛目标 这项研究计划的目的是获得有关分子的知识， 甲状腺生理机制，通过识别和 引起甲状腺激素缺陷的人类遗传错误的特征 调节、合成、运输和作用。异常的基因产物会 在分子水平上进行表征，并将产生动物模型 进行深入的表型分析建议研究五个范畴：（1） 将研究表达促甲状腺素抵抗表型的受试者， 为了鉴定具有降低的生物活性的推定促甲状腺素-β， 以及促甲状腺激素受体缺陷。在某些情况下， 促甲状腺激素抗性家族是以显性遗传的 时尚，也将包括在内。(2)钠/碘同向转运体 测序的两个家庭与碘捕获缺陷和性质的 功能缺陷的特征在于体外表达。在 此外，将使用全基因组纯合性筛选来鉴定 一个具有明显碘化物有机化的阿米什人大家族的基因位点 缺损(3)甲状腺素结合球蛋白缺陷的分子基础， 甲状腺素运载蛋白和白蛋白，将被鉴定和表征。(4)的 甲状腺激素缺乏时甲状腺激素抵抗的病因学 受体β或α缺陷将被调查， 将探索缺陷的辅阻遏物或辅激活物。另外还有按 临床方案将用于确定甲状腺激素的新家庭 将进行超敏反应和实验室研究，以确定 这种综合征的分子基础。(5)最后，基因的作用 甲状腺综合征临床严重程度可变的背景 激素抵抗将被探索，使用具有不同 对甲状腺激素的敏感性突变型甲状腺的体细胞基因转移 激素受体将进行，和转基因小鼠远系繁殖， 检查对甲状腺激素表型表达的影响 阻力

DESCRIPTION: (Adapted from the applicant's abstract). The broad objective of this research proposal is to gain knowledge about the molecular mechanisms of thyroid physiology through the identification and characterization of human genetic errors causing defects of thyroid hormone regulation, synthesis, transport and action. Abnormal gene products will be characterized at the molecular level, and animal models will be generated for in-depth phenotype analysis. Five areas of study are proposed: (1) Subjects expressing the phenotype of thyrotropin resistance will be studied, in order to identify a putative thyrotropin-beta with reduced bioactivity, as well as thyrotropin receptor defects. The mechanism whereby in some families resistance to thyrotropin is inherited in an apparent dominant fashion, will also be included. (2) The sodium/iodide symporter will be sequenced in two families with iodide trapping defect and the nature of the functional defect will be characterized by in vitro expression. In addition, a genome-wide homozygosity screen will be used to identify the gene locus in a large Amish kindred with an apparent iodide organification defect. (3) The molecular basis of defects of thyroxine-binding globulin, transthyretin and albumin, will be identified and characterized. (4) The etiology of resistance to thyroid hormone in the absence of thyroid hormone receptor beta or alpha defects will be investigated, and the possibility of a defective corepressor or coactivator will be explored. In addition, a clinical protocol will be used to identify new families with thyroid hormone hypersensitivity and laboratory studies will be carried out to determine the molecular basis of this syndrome. (5) Finally, the role of genetic background on the variable clinical severity of the syndrome of thyroid hormone resistance will be explored, using mice strains with differing sensitivity to thyroid hormone. Somatic gene transfer of mutant thyroid hormone receptors will be performed, and the transgenic mice outbred to examine the effects on phenotypicexpression of the thyroid hormone resistance.