HYPOPITUITARISM: CLINICAL & MOLECULAR CHARACTERIZATION

哺乳动物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。这些因素引发一系列发育事件，导致成熟的垂体细胞类型，编码这些因素的基因突变或缺失已被证明会导致哺乳动物垂体前叶激素缺乏。这些动物模型的一个一致特征是生长激素缺乏与TSH和/或催乳素缺乏有关。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，在许多病例中，垂体功能没有被仔细评估，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由Pit-1和Prop-1基因点突变引起的人类联合垂体激素缺乏症（CPHD）的遗传基础。我们和其他研究人员也在推定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。这些观察结果表明，这些基因的突变可能不仅是CPHD的常见原因，而且也是“孤立的”生长激素缺乏症的常见原因。此外，其他垂体发育因子（Rpx）的突变或缺失，也“孤立的”生长激素缺乏症。此外，其他垂体发育因子（Rpx、Ptx2和Lhx3）的突变或缺失与垂体激素缺乏有关。本研究将对垂体功能减退症患者进行临床表征，并研究候选基因的结构。对垂体转录因子突变及其多种病理生理机制的研究，有助于增进我们对正常和疾病状态下垂体前叶发育和基因调控的认识。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医师，在那里她是生殖内分泌部门和内分泌临床实验室的主任。对哺乳动物GnRH基因表达（RO1-HD34551）和Pit-1基因功能（R01-DK53977）的研究有独立支持。她还指导了一项CRC协议，以评估和分类垂体功能减退症患者。她积极指导四位BE/BC儿科内分泌学家，一位BE妇产科医生，其中两位由校内内分泌培训资助（T32HD07277）资助，一位由指导资助（K11DK02329）资助，一位由儿童医院指导成功的珍妮韦奖学金资助，在一个充满学术机会的环境中，该奖项将使她能够增加她的指导活动，并加强她自己对以患者为导向的研究的承诺。

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.