Molecular Endocrinology of Parathyroid Disorders Affecting Calcium Homeostasis

Lead Research Organisation: University of Oxford
Department Name: Unknown

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

Parathyroid tumours, which affect 3:1,000 of the adult population, and congenital parathyroid developmental anomalies, which occur in 1:4,000 live births, are major causes of abnormal calcium and bone metabolism. We are investigating the molecular basis of such disorders by the combined use of the positional cloning and functional genomics approaches. Thus, in an integrated programme, we are studying the genetic control of parathyroid development, and the molecular events involved in parathyroid tumourigenesis. These two areas are complementary as tumourigenesis often results from the inappropriate expression of developmental genes. During 1999-2003, we showed that the hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is due to haploinsufficiency of the transcription factor GATA3; defined that a molecular deletional-insertion, involving chromosomes Xq27 and 2p25, causes X-linked hypoparathyroidism (XLHPT), which is due to parathyroid agenesis; and identified a novel gene causing hyperparathyroidism-jaw tumour (HPT-JT) syndrome. In addition, we have established a mouse knockout model for multiple endocrine neoplasia type 1 (MEN1); are generating chiameric mice that will help to establish a mouse knockout model for the HPT-JT syndrome; shown that GATA3 knockout mice represent an HDR phenotype; and that SOX3 knockout mice are likely to have abnormal parathyroid structure, which may contribute to the XLHPT phenotype. We now propose, in a continution of this programme, to elucidate the roles of the MEN1, HPT-JT, GATA3 and SOX3 genes in parathyroid functions and to use the MEN1 mouse model for investigating viral vectors in ex vivo and in vivo gene therapy studies. These studies will increase our understanding of the multi-step pathway in endocrine tumourigenesis and of the mechanisms regulating calcium homeostasis and parathyroid development. My group has made significant contributions to this field which is ideally placed at the basic science and clinical interface, and fits in with the MRC cancer priority area.

Publications

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Devuyst O (2010) Dent's disease. in Orphanet journal of rare diseases

 
Description Collabortive Grant
Amount £120,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 10/2011 
End 10/2012
 
Description EuReGene European Renal Genome Project (10.2m euros across 14 participants)
Amount £500,000 (GBP)
Funding ID 5085 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2005 
End 06/2009
 
Description MRC Clinical Training Fellowship (Newey)
Amount £200,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 07/2007 
End 07/2010
 
Description MRC Clinical Training Fellowship (Walls)
Amount £200,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2006 
End 09/2009
 
Description Marie Curie Fellowship - E Kallay
Amount £80,000 (GBP)
Organisation Marie Sklodowska-Curie Actions 
Sector Academic/University
Country Global
Start 04/2007 
End 03/2008
 
Description PhD Studentship - C Gorvin
Amount £60,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2008 
End 09/2011
 
Description PhD Studentship - K Gaynor
Amount £60,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2007 
End 09/2010
 
Description PhD Studentship - S Mirczuk
Amount £60,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 10/2006 
End 09/2009
 
Description Treat-OA
Amount £500,000 (GBP)
Funding ID 200800 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2008 
End 12/2012
 
Description Wellcome Trust Clinical Training Fellowship - M Javid
Amount £200,000 (GBP)
Funding ID 087332/Z/08/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2008 
End 09/2011
 
Description Brown, S 
Organisation MRC Harwell
Department MRC Mammalian Genetics Unit
Country United Kingdom 
Sector Public 
PI Contribution Undertaken molecular genetic studies and mouse phenotyping analysis together with details for publication.
Collaborator Contribution Brought together different expertise and resources to answer a biological question.
Impact 20457824
 
Description Cheeseman M 
Organisation MRC Harwell
Department MRC Mammalian Genetics Unit
Country United Kingdom 
Sector Public 
PI Contribution Generated mouse model, undertook all studies except for histology.
Impact 19620250
Start Year 2007
 
Description Cox, R 
Organisation Medical Research Council (MRC)
Department The Mary Lyon Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Undertaken molecular genetic studies and mouse phenotyping analysis together with details for publication.
Collaborator Contribution Brought together different expertise and resources to answer a biological question.
Impact Several papers, full details under publications.
 
Description Devuyst, Olivier 
Organisation Catholic University of Louvain
Department Department of Nephrology
Country Belgium 
Sector Academic/University 
PI Contribution Undertaken molecular genetic studies and analysis together with details for publication.
Collaborator Contribution Brought together different expertise and resources to answer a biological question.
Impact 20976470 20946626 19940036
 
Description Dr M P Whyte, USA 
Organisation Washington University in St Louis
Country United States 
Sector Academic/University 
PI Contribution Undertook molecular analysis and detailed scientific studies for the XLHPT project published in JCI 2005.
Impact 19809483 16167084
 
Description Grosveld, F 
Organisation Erasmus University Rotterdam
Department Biomedical Genetics
Country Netherlands 
Sector Academic/University 
PI Contribution Undertaken molecular genetic studies and mouse phenotyping analysis together with details for publication.
Collaborator Contribution Brought together different expertise and resources to answer a biological question.
Impact 20484821
 
Description Lyon MF 
Organisation MRC Harwell
Department MRC Mammalian Genetics Unit
Country United Kingdom 
Sector Public 
PI Contribution Identification of a CaSR mutation together with functional studies.
Impact 15347804
 
Description Manley, N 
Organisation University of Georgia
Department Department of Genetics
Country United States 
Sector Academic/University 
PI Contribution Undertaken molecular genetic studies and mouse phenotyping analysis together with details for publication.
Collaborator Contribution Brought together different expertise and resources to answer a biological question.
Impact 20484821
Start Year 2008
 
Description Rorsman, P 
Organisation University of Oxford
Department Nuffield Department of Clinical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Undertaken molecular genetic studies and analysis together with details for publication.
Collaborator Contribution Brought together different expertise and resources to answer a biological question.
Impact 209498720 19940036
 
Description AMEND Patient Support Group 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Approximately 200 patients and their relatives attended the talk which raised important and interesting questions with discussions thereafter. The venue was at a hotel in Rugby (UK) over a weekend.

Raised interest amongst patients for the need for medical research.
Year(s) Of Engagement Activity 2012
 
Description New York Times 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Gave an interveiw to reporter (E Svoboda) from the New York Times about a paper that we had just published in Journal of Clincial Investigation (October 2005). New York Times article published on 7th February 2006 and entitled "Scientists sort through 'junk' to unravel a genetic mystery".

Increased public awareness.
Year(s) Of Engagement Activity 2006
 
Description Patient support group - AMEND 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Providing input at Annual Association meetings of AMEND. Advice on other issues in my capacity as Patron.

Increases pateint awareness.
Year(s) Of Engagement Activity 2006,2007,2008,2009
 
Description Patient support group - AMEND 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Providing information for news letter.

Increases patient awareness.
Year(s) Of Engagement Activity 2006,2007,2008,2009
 
Description Placement for undergraduate student 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Undergraduate students
Results and Impact Undergraduate student undertook a research project for one month and continued for the next year on a part time basis to complete this for final honors degree.

Degree obtained. Presentation of abstract at national British Endocrine Societies meeting.
Year(s) Of Engagement Activity 2009
 
Description School visit - Oxford High School, Oxford 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact 40 students studying for A levels and GCSEs.

Generated interest in science and medicine with particular emphasis on genetics of cancer.
Year(s) Of Engagement Activity 2008