RESISTANCE TO THYROID HORMONE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 这项临床研究的目标是建立和测试临床方案，这些方案将用于评估广义上定义的甲状腺激素抵抗综合征。甲状腺激素抵抗是终末器官对甲状腺激素反应性降低的综合征。所考虑的情况包括那些干扰正常供应的化学完整的甲状腺激素的生物活性的生理缺陷。这些包括：1)甲状腺激素的细胞膜转运异常；2)前激素3，3，5，5-四碘甲腺原氨酸(T4)转化为活性甲状腺激素的异常；3)3，3，5-三碘甲腺原氨酸(T3)；3)由于TH受体(Tr)？缺陷，被称为经典的甲状腺激素抵抗(RTH)或类似的综合征，但没有tr？基因突变。后者被称为非TR-RTH，与调节甲状腺激素在细胞核的作用的辅助因子的异常有关。这些辅因子在相关的核受体中是常见的，据推测，它们也可能对糖皮质激素的作用产生微妙的抵抗。根据甲状腺功能测试，可能会怀疑这些缺陷。然而，基础甲状腺功能测试不足以做出准确的诊断，需要仔细分析本申请中提出的受试者S的表型。此外，这些综合征的表型特征将为基因测试确立标准，这反过来又可以进行产前诊断，并可能进行早期干预和治疗。这在与重大神经后遗症(例如MCT8突变)相关的缺陷中尤其重要，在这些缺陷中，早期干预可能逆转或阻止相关发现。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objectives of this clinical investigation are to establish and test clinical protocols that will serve to evaluate syndromes of resistance to thyroid hormone as defined in the broadest sense. Resistance to thyroid hormone are syndromes of reduced end-organ responsiveness to thyroid hormone. Conditions under consideration encompass those physioloigcal defects that interfere with the biological activity of a chemically intact thyroid hormone supplied in normal amount. These include: 1) Abnormalities in cell membrane transport of thyroid hormone; 2) Abnormalities in the conversion of the prohormone 3,3 ,5,5 -tetraiodothyronine (thyroxine, T4) into the active thyroid hormone, 3,3 ,5-triiodothyronine (T3) and 3) Abnormalities at the level of nuclear action of T3 due to TH receptor (TR)? defects, known as the classical resistance to thyroid hormone (RTH) or similar syndromes without TR? gene mutations. The latter, termed nonTR-RTH, are associated with abnormalities in cofactors mediating the action of thyroid hormone at the nucleus. These cofactors are common to related nuclear receptors, and it is postulated that they may also produce subtle resistance to glucocorticoid action. These defects may be suspected based on thyroid function tests. However basal thyroid function tests are not sufficient to make an accurate diagnosis and require a careful analysis of the subject s phenotype as proposed in this application. Furthermore characterization of the phenotypes of these syndromes would establish criteria for genetic testing which in turn could allow for prenatal diagnosis and possibly early intervention and treatment. This would be particularly important in defects that are associated with significant neurologic sequelae (e.g. MCT8 mutations) where early intervention may reverse or prevent the associated findings.