Title: Molecular Mechanisms and Therapies for Parathyroid and Neuroendocrine Disorders
Funder: Medical Research Council

Abstract: Our research is focussed on investigating the molecular mechanisms underlying parathyroid and neuroendocrine disorders, with the aim of translating these advances into clinical practice by facilitating improvements in diagnosis and management, and of establishing in vitro and in vivo models for exploring new pharmacological and gene replacement therapies. Parathyroid tumours are common and major causes of abnormal calcium and bone metabolism, and may occur as an isolated endocrinopathy or in association with neuroendocrine tumours (NETs) of the pancreas and pituitary, as in multiple endocrine neoplasia type 1 (MEN1). During 2004-2009, we showed that: mutational analysis can solve diagnostic errors due to MEN1 phenocopies which occur in 5% of families; asymptomatic children with MEN1 mutations harbour non-functioning pancreatic NETs, thereby indicating a revision of the current international guidelines for screening; patients with germline MEN1 mutations may develop only parathyroid tumours and not NETs, implicating a role for genetic modifiers; pituitary NETs with loss of the MEN1 gene have abnormalities of proliferative (Wnt/beta-catenin) and apoptotic (Bcl2) pathways, down-regulation of tumour suppressor microRNAs (miR-15a-miR16-1) and upregulation of oncogenic microRNAs (miR130b); Men1 gene replacement therapy can decrease the proliferation rate of pituitary NETs in Men1+/- mice; inactivating mutations of the calcium-sensing receptor (CaSR), a G-protein coupled receptor (GPCR), which cause familial benign hypocalciuric hypercalcaemia type 1 (FBHH1) can be associated with parathyroid tumours in adults; an allosteric modulator of the CaSR can correct hypocalcaemia in a mouse model with an activating CaSR mutation that represents a model for autosomal dominant hypocalcaemic hypercalciuria type 1 (ADHH1); mutations in the G-protein, Galpha11, are associated with FBHH2 and ADHH2; and patients with FBHH3 have involvement of an as yet unidentified gene on chromosome 19q13. We now propose in a continuation of this programme to elucidate: 1) the genetic mechanisms and pathways underlying parathyroid and neuroendocrine tumourigenesis, by investigating the roles of the Galpha11, FBHH3, and MEN1 genes, and microRNAs; and 2) undertake pre-clinical studies using in vitro and in vivo models that would facilitate the implementation of new treatments e.g. targeted-peptides, gene therapy and microRNA therapy, for NETs and disorders of calcium homeostasis. Knowledge gained from these studies, will contribute to improved diagnostic and therapeutic strategies in these endocrine disorders. My group has made internationally leading contributions to this field which is ideally placed at the basic science and clinical interface, and fits with the MRC strategic priorities of: genetics and disease; and translation of research.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE