RESISTANCE TO THYROID HORMONE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。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。这些异常包括：1)甲状腺激素的细胞膜转运异常；2)前激素3，3‘，5，5’-四碘甲状腺原氨酸(T4)转化为活性甲状腺激素的异常；3)3，3‘，5-三碘甲状腺原氨酸(T3)的核活动异常；3)TH受体？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，被认为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。这些辅因子被认为是相关核受体共有的，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往往不足以做出准确的诊断，而且往往需要仔细分析受试者的表型。此外，这些综合征的表型特征将建立基因测试的标准。基因异常的识别可能允许产前诊断和可能的早期干预和治疗。这在与重大神经系统Sequella相关的缺陷(例如MCT8突变)中尤其重要，因为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 responsivieness 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 a 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 considered to be associated with abnormalities in cofactors mediating the action of thyroid hormone at the nucleus. These cofactors are considered to be 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 often the basal thyroid function tests are not sufficient to make an accurate diagnosis and often may require a careful analysis of the subject's phenotype. Furthermore characterization of the phenotype of these syndromes would establish criteria for genetic testing. Identification of the genetic abnormality may allow for prenatal diagnosis and possible early intervention and treatment. This would be particularly important in the defects that are associated with significant neurologic sequella (e.g. MCT8 mutations) as early intervention may reverse or prevent the associated findings