THYROID PHYSIOLOGY STUDIES OF INHERITED DISORDERS

描述：(申请人提供)本研究的总体目标 建议通过以下方式提高我们对甲状腺生理学的理解 对处于关键调控过程中的遗传缺陷患者的详细研究 结合动物模型的补充研究。更具体地说，一个 建议采用临床和实验室双重方法研究两种激素 抵抗综合征、对甲状腺激素(RTH)的抵抗和对 促甲状腺激素(RTSh)，其重要亚型的病因仍然存在 未知。 无TH受体(TR)基因突变的RTH的病因将是 下定决心。这一假设基于初步数据，即非TR-RTH涉及一种 其他核受体共有的辅因子将被检测。1)临床 研究将寻找对糖皮质激素和性激素的抵抗力。2) 携带和不携带tr基因突变的RTH受试者的成纤维细胞 检查他们对TH和地塞米松反应的表型差异， 使用微阵列。3)将检查患有非TR-RTH的家庭是否与 候选基因。4)从非TR-RTH成纤维细胞中分离的辅因子 通过下拉技术的主题将被分析。此外，牵涉到 在RTH表型变异中的辅助因素将通过以下方面进行研究：1) 具有相同TRB基因突变的大家系分析 候选辅因子基因的Rth表型。2)将小鼠与靶标杂交 不同TH敏感性小鼠品系TRJ3基因突变的研究 确定RTH表型的可能修饰物。 RTSh的特征是血清TSH水平升高，存在 正常或发育不良的甲状腺。在美国和欧洲，只有20% 的受试者在TSH受体基因上发生了功能缺失突变。 5个以遗传为主的RTSh大家族，其中 其他5个候选基因(TSH受体、Pax8、TTF-1、TTF-2和GSA)已经被 排除，将通过全基因组筛查进行分析。在地方性碘中 乌班吉(非洲)的贫乏地区，RTSh表现为粘液水肿性 无菌克汀病，尽管存在正常的甲状腺 位置和很高的血清TSH水平。相比之下，甲状腺功能正常的受试者 大小不一的甲状腺肿。这种地方性的RTSh的原因将是 下定决心。将检查TSH受体基因是否可能发生突变。这个 H202产生THOX基因功能获得性突变的可能性 将进行探索，基于它在 杂合子状态，可能导致纯合子的腺体破坏。

DESCRIPTION: (provided by applicant) The broad objective of this research proposal is to improve our understanding of thyroid physiology through the detailed study of patients with genetic defects at key regulatory processes, in combination with complementary studies in animal models. More specifically, a dual clinical and laboratory approach is proposed to study two hormone resistance syndromes, resistance to thyroid hormone (RTH) and resistance to thyrotropin (RTSH), for which the etiologies of important subtypes remain unknown. The etiology of RTH without TH receptor (TR) gene mutations (nonTR-RTH) will be determined. Th hypothesis, based on preliminary data, that nonTR-RTH involves a cofactor common to other nuclear receptors will be examined. 1) Clinical studies will search for resistance to glucocorticoid and sex hormone. 2) Fibroblasts from RTH subjects with and without TR gene mutations will be examined for phenotypic differences in their responses to TH and dexamethasone, using microarrays. 3) Families with nonTR-RTH will be examined for linkage to candidate genes. 4) Cofactors isolated from the fibroblasts of nonTR-RTH subjects by pull down techniques will be analyzed. Furthermore, the involvement of cofactors in the variability of the RTH phenotype will be studied by: 1) Analysis of large families with the same TRB gene mutation, for linkage of the RTH phenotype to candidate cofactor genes. 2) Crossing of mice with a targeted TRJ3 gene mutation with mice Strains of different TH sensitivity in order to identify putative modifiers of the RTH phenotype. RTSH is characterized by an elevated serum TSH level in the presence of a normal or hypoplastic thyroid gland. In the USA and in Europe only 20 percent of subjects with RTSH have loss-of-function mutations in the TSH receptor gene. Five large families with dominantly inherited RTSH, in which the involvement of 5 other candidate genes (TSH receptor, Pax8, TTF-1, TTF-2 and GSa) has been ruled out, will be analyzed by genome-wide screening. In the endemic iodine deficient region of the Ubangui (Africa), RTSH manifests as myxedematous agoitrous cretinism despite the presence of a thyroid gland in the normal location and very high serum TSH levels. In contrast, euthyroid subjects have goiters of variable sizes. The cause of this endemic form of RTSH will be determined. The TSH receptor gene will be examined for possible mutations. The possibility for a gain-of-function mutation in the H202 generating-THOX gene will be explored, based on its selection for iodide retention in the heterozygous state that could cause gland destruction in homozygotes.