Molecular Mechanisms and Therapies for Parathyroid and Neuroendocrine Disorders

内分泌腺分泌的激素异常会扰乱人体许多过程的调节，从而引起不同器官的疾病。甲状旁腺激素（PTH）的紊乱很好地说明了这一点，PTH通过控制从肠道吸收、沉积到骨骼和细胞以及从肾脏排泄的量之间的平衡来调节体内钙。甲状旁腺肿瘤引起的甲状旁腺激素分泌过多，影响3:1000的成年人和1%的绝经后妇女，是血浆钙升高的主要原因，可能与肾结石、肾衰竭、骨质疏松和溃疡有关。此外，甲状旁腺肿瘤可与其他涉及胰腺和垂体神经内分泌细胞的内分泌肿瘤联合发生。这些神经内分泌肿瘤也可能作为孤立的内分泌病变发生，影响5.5万名成年人。胰腺神经内分泌肿瘤可伴有溃疡、腹泻和低血糖引起的癫痫发作；垂体神经内分泌肿瘤可能与不孕症、阳痿、高血压和糖尿病有关。目前对这些内分泌肿瘤的治疗并不总是有效，更好地了解其原因（可能有遗传基础）将有助于改进诊断和治疗。因此，我们一直在进行研究，以确定这些基因，目的是阐明这些甲状旁腺和神经内分泌肿瘤疾病的潜在机制。在这些研究过程中，我们描述了14种钙稳态和骨代谢紊乱、肾结石和内分泌肿瘤的遗传异常和机制。我们还将这些进步转化为：改善诊断和管理；制定指导方针;在小鼠内分泌肿瘤模型中建立基因替代疗法的原理证明；并识别细胞信号通路的异常。我们现在提议，作为这一计划的延续，进一步阐明我们最近发现的基因的功能，并开发药物设计和基因治疗的新途径。这可能会对甲状旁腺和神经内分泌肿瘤、肾结石、肾功能衰竭和骨质疏松症患者的治疗产生进一步的临床影响。研究结果发表在高质量的期刊上，在国内和国际会议上发表，并成为书籍章节和评论文章的基础。申请人还向媒体（如纽约时报）、患者支持团体（修订）提供了专家信息，他将继续承担这一工作。

Abnormal hormone secretion from endocrine glands can disrupt the regulation of many body processes, thereby causing diseases in different organs. This is well illustrated by disorders of parathyroid hormone (PTH) which regulates body calcium, by controlling the balance between the amounts that are absorbed from the gut, deposited into bone and into cells, and excreted from the kidney. Over-secretion of PTH due to parathyroid tumours, which affect 3:1,000 of the adult population and 1% of postmenopausal women, is the major cause of a rise in plasma calcium and may be associated with kidney stones, renal failure, osteoporosis and ulcers. Moreover, parathyroid tumours can occur in association with other endocrine tumours that involve neuroendocrine cells of the pancreas and pituitary. These neuroendocrine tumours may also occur as isolated endocrinopathies that affect 5.5:1,000 adults. The pancreatic neuroendocrine tumours may be associated with ulcers, diarrhoea, and seizures due to a low plasma glucose; and the pituitary neuroendocrine tumours may be associated with infertility, impotence, high blood pressure and diabetes. Current treatments for these endocrine tumours are not always effective, and a better understanding of their causes, which are likely to have a genetic basis, will facilitate improvements in diagnosis and treatments. We have therefore been pursuing studies to identify these genes with the aims of elucidating the underlying mechanisms in these disorders of parathyroid and neuroendocrine tumours. In the course of these studies we have characterised the genetic abnormalities and mechanisms for 14 disorders of calcium homeostasis and bone metabolism, kidney stones and endocrine tumours. We have also translated these advances to: improve diagnosis and management; formulate guidelines; establish proof of principle for gene replacement therapy for endocrine tumours in a mouse model; and identify abnormalities in cellular signalling pathways. We now propose, in a continuation of this programme, to elucidate further the functions of the genes that we have recently identified, and to develop new avenues for drug design and gene therapy. This is likely to have further clinical impacts in the management of patients with parathyroid and neuroendocrine tumours, kidney stones, renal failure and osteoporosis. The results are published in high quality journals, presented at national and international conferences, and form the basis of contributions to book chapters and review articles. The applicant has also provided expert information to the media (e.g. New York Times), patient supports groups (AMEND), and he will continue to undertake this.