MOLECULAR MECHANISMS OF THYROID HORMONE ACTION

描述：（改编自申请人摘要）耐药综合征 甲状腺激素的特点是甲状腺激素水平升高， 在几乎所有的病例中，TSH分泌不当都是由于 TR-b基因座。对这些自然发生的TR突变的体外研究 对RTH综合征产生了有益的见解。可惜 这些研究对患者疾病的普遍性并不总是清楚的 并且由于它们的人工性质可能并不总是安全的。混杂 这些问题是RTH的临床异质性， 突变和建议，至少有两个不同的品种的RTH是 在人类中发现：全身性RTH（GRTH）和中枢性RTH（CRTH）。最近，一个TR 已经描述了小鼠中的基因敲除模型，其具有与 RTH，但也显示出一些显着的差异。这种常染色体隐性遗传的 模型实际上在病理生理学上不同于绝大多数 由一个TR-β等位基因表达突变型TR的RTH患者 主要干扰其余正常TR的基因表达。几 还研究了导致RTH的突变TR-β过表达的体内模型， 但不幸的是， 表达可能不会重现在RTH患者中发现的表达。鉴于这些 限制，研究人员的实验室已经开始开发小鼠RTH 模型通过引入点突变到TR-β基因座通过同源 重组本建议有三个目的，旨在了解 TR在体内的配体非依赖性活性在发生中是重要的， 以及是否选择性的形式，中央RTH（CRTH），是一个离散的 临床实体通过为研究提供遗传上同质的背景， 广泛分析不同组织中基因表达的能力， 模型（目标1和2）补充了正在进行的人类RTH综合征研究 (Aim 3）。

DESCRIPTION: (Adapted from the applicant's abstract) The syndrome of resistance to thyroid hormone is characterized by elevated thyroid hormone levels and inappropriate TSH secretion due in almost all cases to point mutations in the TR-b locus. Studies of these naturally occurring TR mutations in vitro have yielded useful insights into the syndrome of RTH. Unfortunately, the generalizability of these studies to the patient's disorder is not always clear and because of their artificial nature may not always be secure. Confounding these issues are the clinical heterogeneity of RTH in families with the same mutation and the suggestion that at least two distinct varieties of RTH are found in man: generalized RTH (GRTH) and central RTH (CRTH). Recently, a TR knockout model in mice has been described having some features in common with RTH but also displaying some significant differences. This autosomal recessive model is in fact pathophysiologically distinct from the vast majority of patients with RTH where a mutant TR expressed from one TR-beta allele dominantly interferes with gene expression by the remaining normal TRs. A few in vivo models of mutant TR-beta overexpression causing RTH have also been described but unfortunately the level and tissue distribution of mutant TR-beta expression may not reproduce that found in RTH patients. Given these limitations, the investigator's laboratory has begun to develop mouse RTH models by introducing point mutations into the TR-beta locus by homologous recombination. This proposal has three aims directed at understanding whether the ligand-independent activity of the TR in vivo is important in the genesis of RTH and whether the selective form, central RTH (CRTH), is a discrete clinical entity. By providing a genetically homogenous background for study and the ability to extensively analyze gene expression in different tissues, these models (Aim 1 and 2) complement ongoing studies in humans with the RTH syndrome (Aim 3).