Molecular Mechanisms and Therapies for Parathyroid and Neuroendocrine Disorders

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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.