HYPOPITUITARISM: CLINICAL & MOLECULAR CHARACTERIZATION

哺乳动物的垂体发育和激素表达受垂体特异性转录因子控制，包括：Rpx、Lhx3、Prop-1和Pit-1。这些因素启动了一系列发育事件，导致成熟的垂体细胞类型，编码这些因素的基因的突变或缺失已被证明导致哺乳动物的垂体前叶激素缺乏。这些动物模型的一个一致特征是GH缺乏与TSH和/或催乳素缺乏相关。许多患者被描述为完全或部分缺乏这些细胞类型的激素分泌。然而，在许多情况下，没有仔细评估垂体功能，患者经常被诊断为‘特发性’生长激素缺乏症。我的实验室和其他人已经描述了人类由于Pit-1和Prop-1基因点突变导致的混合性垂体激素缺乏症(CPHD)的遗传基础。我们和其他人还在推测为特发性生长激素缺乏症的患者中发现了Pit-1和Prop-1突变。这些观察表明，这些基因的突变可能不仅是慢性阻塞性肺疾病的常见原因，也是“孤立的”生长激素缺乏症的常见原因。此外，其他垂体腺发育因子(RPX)的突变或缺失也是‘孤立的’GH缺乏症。此外，其他垂体发育因子(RPx、Ptx2和Lhx3)的突变或缺失也与垂体激素缺乏有关。这项建议将对垂体功能低下的患者进行临床特征描述，并调查候选基因的结构。研究垂体转录因子的突变及其不同的病理生理机制将有助于我们更好地了解正常和疾病状态下垂体前叶的发育和基因调控。候选人是哈佛医学院儿科学副教授和波士顿儿童医院的副内科医生，在那里她是生殖内分泌部和内分泌临床实验室的主任。她在哺乳动物GnRH基因表达(RO1-HD34551)和Pit-1基因功能(R01-DK53977)方面有独立的支持。她还指导了一项CRC方案，以评估和分类垂体功能低下症患者。她积极指导四位BE/BC儿科内分泌科医生，一位BE/BC儿科妇产科医生，其中两位由校内内分泌培训基金(T32HD07277)资助，一位由导师资助(K11DK02329)资助，另一位由儿童医院简威奖学金资助(K11DK02329)。

Pituitary development and hormone expression in mammals is controlled by pituitary-specific transcription factors including: Rpx, Lhx3, Prop-1 and Pit-1. These factors initiate a cascade of development events resulting in mature pituitary cell-types and mutation or deletion of the genes encoding these factors have been shown to result in anterior pituitary hormone deficiency in mammals. A consistent feature of these animal models is GH deficiency associated with either TSH and/or prolactin deficiency. Many patients have been described with complete or partial deficiency of hormone secretion from these cell types. However, in many cases, the pituitary function has not been carefully evaluated and patients are frequently diagnosed as having 'idiopathic' GH deficiency. My laboratory and others have described a genetic basis for combined pituitary hormone deficiency (CPHD) in man due to point mutations in the Pit-1 and Prop-1 genes. We and others have also discovered Pit-1 and Prop-1 mutations in patients with presumed idiopathic GH deficiency. These observations demonstrate that mutations in these genes may be a frequent cause of not only CPHD, but also 'isolated' GH deficiency. In addition, mutation or deletion of other pituitary developmental factors (Rpx, also 'isolated' GH deficiency. In addition, mutation or deletion of other pituitary developmental factors (Rpx, Ptx2 and Lhx3) has been associated with pituitary hormone deficiencies. This proposal will clinically characterize patients with hypopituitarism and investigate the structure of candidate genes. Study of mutations in pituitary transcription factors and their diverse pathophysiological mechanisms should increase our understanding of anterior pituitary gland development and gene regulation in normal and disease states. The candidate is an Associate Professor of Pediatrics at Harvard Medical School and an Associate Physician at Children's Hospital, Boston, where she is the director of the reproductive endocrine unit and endocrine clinical laboratories. She has independent support to study GnRH gene expression (RO1-HD34551) and Pit-1 gene function (R01-DK53977) in mammals. She also directs a CRC protocol to evaluate and categorize patients with hypopituitarism. She actively mentors four BE/BC pediatric endocrinologists, a BE obstetrician-gynecologist, two of whom are funded by the intramural Endocrine training grant (T32HD07277), one funded by a mentored grant (K11DK02329), one by a Janeway fellowship award from Children's Hospital mentoring success, in an environment rich with academic opportunities, this award will allow her to increase her mentoring activities and to enhance her own commitment to patient- oriented research.