MOLECULAR MECHANISMS OF THYROID HORMONE ACTION

描述：(改编自申请者的摘要)抵抗症 甲状腺激素的特点是甲状腺激素水平升高和 TSH分泌不当在几乎所有病例中都是由于 Tr-b基因座。对这些自然产生的tr基因突变的体外研究 对RTH综合征有了有用的见解。不幸的是， 这些研究对患者疾病的概括性并不总是很清楚 而且由于它们的人工本性可能并不总是安全的。令人困惑 这些问题是RTH在有相同疾病的家庭中的临床异质性 突变和至少两种不同的RTH变种是 人类发现：全身性RTH(GRTH)和中枢性RTH(CRTH)。最近，一棵树 小鼠的基因敲除模型被描述为具有一些共同的特征 但也表现出一些显著的差异。这种常染色体隐性遗传 模型实际上在病理生理上有别于绝大多数 突变的tr来自一个tr-β等位基因的患者 主要通过其余正常的TRs干扰基因的表达。几个 导致RTH的突变型TR-β过表达的体内模型也被 描述了突变的tr-β的水平和组织分布 在RTH患者中的表达可能不会重现。考虑到这些 由于存在局限性，研究人员的实验室已经开始研发小鼠RTH 通过同源基因将点突变引入到tr-β基因座的模型 重组。这项提议有三个目的，旨在了解 受体在体内的不依赖配体的活性在其发生中起重要作用。 以及选择形式中央RTH(CRTH)是否是离散的 临床实体。通过为研究和研究提供遗传同质的背景 广泛分析不同组织中基因表达的能力，这些 模型(目标1和目标2)补充了正在进行的人类RTH综合征研究 (目标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).