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的原因之一 发育迟缓，集体发病率为1：3- 4 000。早期诊断 治疗对于预防终身衰弱至关重要， 在治疗的年龄之间存在反比关系， 开始和最终的心理测量结果。甲状腺激素在全球范围内发挥作用， 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 调节过程依赖于下丘脑的激素级联， 脑下垂体和甲状腺。虽然不太常见，但由于垂体 缺陷对新生儿筛查提出了特殊的诊断挑战 方案，导致治疗延误。目前还没有动物模型 垂体CH，从中人们可以深入了解这些问题， 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、男性生育能力低下和行为异常 在一个犬科家庭里TRH刺激试验和激素分析表明， 这种疾病是由脑垂体无法增加 促甲状腺激素（TSH）分泌适当的受影响的狗，尽管低 甲状腺激素浓度这项调查的长期目标是 为了表征和使用这种独特的人类CH动物模型， 了解正常垂体功能，非甲状腺介导的功能， 促甲状腺激素以及TRH信号传导缺陷的发病机制。立即 研究人员建议确定这种疾病的分子基础， 以期为今后的发病机制研究提供更多的意义。的 这项建议的具体目标是：1）维持一个CH的繁殖群体 狗和执行交配，扩大CH家庭的方式，是最 为候选基因连锁研究提供信息，2）检查TRH介导的 促甲状腺激素分泌信号转导途径的研究 受影响的和正常的狗细胞中的钙离子电流，以产生 候选基因假说，3）研究犬的分子基础， CH通过检查候选疾病基因。最初的重点将是分析 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.