MOLECULAR BASIS OF CONGENITAL THYROTROPIN DEFICIENCY

描述(改编自申请人的描述)：先天性甲状腺功能减退症 (CH)是可预防的精神和成长的最常见原因之一 发育迟缓，总发生率为1：3-4,000。早期诊断 治疗是预防终生虚弱的关键，因为 在接受治疗的年龄之间存在着相反的关系 开始的和最终的心理测量结果。甲状腺激素在全球范围内作用于 激活新陈代谢，是正常生长和新生儿发育所必需的 大脑和免疫系统。甲状腺激素的分泌是一种精细的 依赖于下丘脑荷尔蒙级联的调节过程， 脑下垂体和甲状腺。虽然不太常见，但由于脑下垂体引起的CH 缺陷给新生儿筛查带来了特殊的诊断挑战 方案，导致治疗延误。到目前为止还没有动物模型 脑下丘脑，从中可以洞察到一些问题，如 促甲状腺激素释放激素(TRH)介导的器官功能 脑下垂体。一种遗传形式的CH，导致不成比例的 发现了生长迟缓、男性不育和行为异常。 在一个犬科动物家庭里。TRH刺激试验和激素分析证实 这种疾病是由于脑下垂体不能增加 尽管受影响的狗促甲状腺激素(TSH)水平较低，但仍能正常分泌 甲状腺激素浓度。这项调查的长期目标是 表征和使用这一独特的人类CH动物模型以更好地 了解正常的垂体功能，非甲状腺介导的功能 促甲状腺激素，以及TRH信号缺陷的发病机制。立刻， 研究人员建议确定这种疾病的分子基础 以期对今后的发病机制研究有更多的意义。这个 这项建议的具体目标是：1)保持一个繁育群体 狗和表演交配，这扩大了CH家族以一种最 为候选基因连锁研究提供信息，2)检测TRH介导的 测定TRH刺激下TSH分泌的信号转导途径 受影响和正常犬细胞的钙离子电流以便产生 候选基因假说，以及3)研究犬的分子基础 通过检查候选疾病基因。最初的重点是分析 编码TRH受体的候选基因。

DESCRIPTION (Adapted from applicant's description): Congenital hypothyroidism (CH) is one of the most common causes of preventable mental and growth retardation, with a collective incidence of 1:3-4,000 births. Early diagnosis and treatment is critical to the prevention of life-long debility because there is an inverse relationship between the age at which treatment is initiated and eventual psychometric outcomes. Thyroid hormone acts globally to activate metabolism and is required for normal growth and neonatal development of the brain and immune system. Thyroid hormone secretion is a finely regulated process that depends on a hormone cascade of the hypothalamus, pituitary gland, and thyroid gland. Though less common, CH due to pituitary defects present a particular diagnostic challenge to neonatal screening programs, resulting in delay of treatment. There has been no animal model of pituitary CH from which one might gain insight into such issues as the loss of thyrotropin-releasing hormone (TRH)-mediated functions in organs other than the pituitary gland. An inherited form of CH resulting in disproportionate growth delay, male hypofertility, and behavioral abnormalities was identified in a canine family. TRH-stimulation testing and hormone analysis demonstrated that the disorder is caused by failure of the pituitary gland to increase thyrotropin (TSH) secretion appropriately in affected dogs in spite of low thyroid hormone concentrations. The longterm goals of this investigation are to characterize and use this unique animal model of human CH to better understand normal pituitary function, non-thyroid gland-mediated functions of thyrotropin, and the pathogenesis of deficient TRH signaling. Immediately the investigators proposed to determine the molecular basis of the disorder in order to give added significance to future studies of pathogenesis. The specific aims of this proposal are: 1) to maintain a breeding colony of CH dogs and to perform matings which extend the CH family in a way that is most informative for candidate gene linkage studies, 2) to examine the TRH-mediated signal transduction pathway of TSH secretion by measuring TRHstimulated calcium ion currents in affected and normal dog cells in order to generate candidate gene hypotheses, and 3) to investigate the molecular basis of canine CH by examining candidate disease genes. Initial emphasis will be analysis of the candidate gene encoding the TRH receptor.