Replication of fibroblast growth factor and heparan sulphate signalling by thyroid hormone during bone development

Lead Research Organisation: Imperial College London
Department Name: Unlisted

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.

Publications

10 25 50
 
Description TSH supression in thyroid cancer patients
Geographic Reach Europe 
Policy Influence Type Influenced training of practitioners or researchers
Impact TSH suppression is not detrimental in man and premenopausal women but may be detrimental in postmenopausal women. Highlighting importance of osteoporosis surveillance in post menopausal women treated for differentiated thyroid cancer.
 
Description ARC Equipment Grant
Amount £35,000 (GBP)
Organisation Versus Arthritis 
Start 01/2008 
End 12/2008
 
Description BBSRC Research Grant (F021704/1)
Amount £596,299 (GBP)
Funding ID BB/F021704/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 03/2009 
End 04/2012
 
Description BTF Research Grant
Amount £10,000 (GBP)
Organisation British Thyroid Foundation (BTF) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2004 
End 01/2006
 
Description BTF Research Grant
Amount £10,000 (GBP)
Organisation British Thyroid Foundation (BTF) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2007 
End 12/2007
 
Description Hammersmith Hospitals Trustees' Equipment Grant
Amount £20,000 (GBP)
Organisation Imperial College Healthcare NHS Trust 
Sector Hospitals
Country United Kingdom
Start 01/2007 
End 12/2007
 
Description Hammersmith Hospitals Trustees' Research Grant
Amount £10,000 (GBP)
Organisation Imperial College Healthcare NHS Trust 
Sector Hospitals
Country United Kingdom
Start 01/2004 
End 12/2006
 
Description MRC Project Grant
Amount £498,507 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 04/2009 
End 03/2013
 
Description Sir Jules Thorn Trust PhD Studentship
Amount £75,000 (GBP)
Organisation Sir Jules Thorn Charitable Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2008 
End 09/2011
 
Description Wellcome Trust Project Grant (GR076584)
Amount £326,126 (GBP)
Funding ID GR076584 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2006 
End 05/2008
 
Title Model of cell type specific hypothyroidism 
Description We have generated floxed-Dio3 mice (pROSA26PA/rD3) that over-express the type 3 deiodinase enzyme, which inactivates thyroid hormones, following excision of the floxed cassette 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact We have obtained chondrocyte- (type II collagen-Cre (Col2-cre)), osteoblast- (osteocalcin-Cre(OC-cre)) and osteoclast- (M lysozyme-cre (LysM-cre)) specific Cre mice Thus, we now have the reagents to characterize the role of unliganded thyroid hormone receptors in the 3 bone cell types chondrocytes, osteoblasts and osteoclasts. Furthermore this model system can be used to investigate the role of hypothyroidism in the development of other key thyroid hormore responsive tissues such as the brain. 
 
Title Quantitative Faxitron analysis of the skeleton 
Description We purchased a Faxitron MX20 Digital X-ray unit and have developed a novel and rapid method to determine skeletal morphometric parameters and bone mineral content at a resolution of 10 micron. 
Type Of Material Technology assay or reagent 
Year Produced 2008 
Provided To Others? Yes  
Impact We have already used this method in a number of in vivo models of skeletal disease generated by other groups. Furthermore, we are currenty performing a pilot project with the Sanger Institute screening 100 consecutive lines, from the Knockout Mouse Project , for skeletal abnormalities. This new methodology was presented at the European Calcified Tissue Society Osteoclast Workshop, Aberdeen in 2008 and as a result we contributed a chapter on quantitative Faxitron analysis to the second addition of "Bone Research Protocols" (Humana Press). 
 
Title Skeletal mechanical testing 
Description We purchased an Instron 5543 load frame and have developed bespoke fittings to facilitate 3 point bending, compression and torsional analysis of specimens from in vivo models of skeletal disease. We have also designed custom software to calculate standard material strength parameters in these samples. 
Type Of Material Improvements to research infrastructure 
Year Produced 2009 
Provided To Others? Yes  
Impact Development of this new methodology has facilitated collaboration with the Kennedy Institute of Rheumatology and the detailed analysis of multiple in vivo models of fracture healing. Furthermore, we are using this methodology in a pilot project with the Sanger Institute screening 100 consecutive lines, from the Knockout Mouse Project. 
 
Description Anita Boelen: Role of the type 3 deiodinase in macrophage activity 
Organisation Academic Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution Generation of the Rosa26/D3 mouse line and cross with LysM-Cre (monocyte/macrophage lineage specific)
Collaborator Contribution Established S. pneumoniae infection protocol
Impact Experiments in progress
Start Year 2011
 
Description Bone phenotype in mice with severe dominant negative mutations of thyroid hormone receptor alpha and beta 
Organisation National Cancer Institute (NCI)
Country United States 
Sector Public 
PI Contribution We have characterised the skeletal phenotypes in these mice during developing (PMID: 17488972 ). We are currently characterizing the severe adult skeletal phenotype in these mice.
Collaborator Contribution Generation of thyroid hormone receptor knockin mice harbouring a severe dominant negative mutations of either thyroid hormone receptor alpha (TRaPV/+) or thyroid hormone receptor beta (TRb(PV/PV). The have provided skeletal samples from these mice.
Impact Publications PMID: 16051666, PMID: 16150908, PMID: 19584945, PMID: 16862217
 
Description David Carling Role of type 3 deiodinase in hepatocytes 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Academic/University 
PI Contribution Generation of Rosa26/D3 mice. These mice were crossed with Alb-Cre mice to generate mice that express the type 3 deiodinase ion hepatocytes. Analysis of phenotype.
Collaborator Contribution Alb-Cre mice and analysis of metabolic phjenotype
Impact In progress
Start Year 2011
 
Description Development of high resolution skeletal imaging in mice 
Organisation Queen Mary University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution In collaboration we have analysed the skeletal phenotype of a number genetically modified mice.
Collaborator Contribution Back-scattered electron scanning electron microscopy and confocal microscopy. Continued collaboration has been vital in the skelatal phenotyping of genetically modified mice.Development of key statistical analysis software used in quantitative back-scattered electron scanning electron microscopy
Impact Development of quantitative digital Faxitron analysis and in performing back-scattered electron microscopy. Co-aurthors on the following publications. PMID: 17932107 PMID: 17488972 PMID: 17327419 PMID: 19584945, PMID: 20368437
 
Description Development of high resolution skeletal imaging in mice 
Organisation University College London
Department Eastman Dental Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution In collaboration we have analysed the skeletal phenotype of a number genetically modified mice.
Collaborator Contribution Back-scattered electron scanning electron microscopy and confocal microscopy. Continued collaboration has been vital in the skelatal phenotyping of genetically modified mice.Development of key statistical analysis software used in quantitative back-scattered electron scanning electron microscopy
Impact Development of quantitative digital Faxitron analysis and in performing back-scattered electron microscopy. Co-aurthors on the following publications. PMID: 17932107 PMID: 17488972 PMID: 17327419 PMID: 19584945, PMID: 20368437
 
Description Intrauterine transplantation of human fetal mesenchymal stem cells reduces fractures in osteogenesis imperfecta mice 
Organisation Imperial College London
Department Institute of Reproductive and Developmental Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution We have assisted in the skeletal phenotyping of these mice.
Collaborator Contribution Developed a murine model for treatement of osteogenesis imperfecta by intrauterine stem cell transplantation.
Impact Initial studies have been published (PMID: 17967940) and PMID: 21088133
Start Year 2007
 
Description Role of Deiodinase enzymes in the skeleton 
Organisation Dartmouth College
Department Geisel School of Medicine
Country United States 
Sector Academic/University 
PI Contribution We have characterised the skeletal phenotypes of mice lacking the type 2 deiodinase and mice lacking both the Type 1 and type 2 deiodinase.
Collaborator Contribution Generation of Deiodinase 1, 2 and 3 knockout mice. Skeletal samples from D2KO and D1/D2KO mice have been provided.
Impact Manuscript: "Optimal bone strength and mineralization requires the type 2 iodothyronine deiodinase in osteoblasts" Proc Natl Acad Sci U S A. 2010 107(16):7604-9 PMID: 20368437
 
Description Role of natural killer T cells in the regulation of bone turnover 
Organisation Imperial College London
Department Centre for Haematology
Country United Kingdom 
Sector Academic/University 
PI Contribution We have contributed to the design of this study and performed the skeletal analysis.
Collaborator Contribution Investigation of the role of invariant natural killer T (iNKT) cells in adult bone remodelling by analysing mice deficient in iNKT cells.
Impact Revised manuscript submitted to Journal of Imunology "Invariant NKT cells regulate osteoclast development and function"
Start Year 2006
 
Description Role of thyroid stimulating hormone in bone 
Organisation University of Chicago
Department J. P. Kennedy Mental Retardation and Developmental Disabilities Center
Country United States 
Sector Academic/University 
PI Contribution We characterised the skeletal phenotype in 2 different congenitally hypothyroid mice. Pax8-/- have no thyroid tissue, a 2000 fold elevation of thyroid stimulating hormone (TSH) and a functional TSH receptor. hyt/hyt mice have a severly hypoplastic thyroid, a 2000 fold elevation of TSH but no functional TSH receptor. As a consequence we were able to demostrated that TSH does not have an important role in bone.
Collaborator Contribution Provision of hyt/hyt mice that lack functional TSH receptors. Assistance in the design of experiments that address the role of TSH in bone.Provision of Pax8 knockout mice for this study
Impact This study is published PMID: 17932107
 
Description Role of thyroid stimulating hormone in bone 
Organisation University of Lyon
Department Institute of Functional Genomics
Country France 
Sector Academic/University 
PI Contribution We characterised the skeletal phenotype in 2 different congenitally hypothyroid mice. Pax8-/- have no thyroid tissue, a 2000 fold elevation of thyroid stimulating hormone (TSH) and a functional TSH receptor. hyt/hyt mice have a severly hypoplastic thyroid, a 2000 fold elevation of TSH but no functional TSH receptor. As a consequence we were able to demostrated that TSH does not have an important role in bone.
Collaborator Contribution Provision of hyt/hyt mice that lack functional TSH receptors. Assistance in the design of experiments that address the role of TSH in bone.Provision of Pax8 knockout mice for this study
Impact This study is published PMID: 17932107
 
Description Skeletal analysis of mice lacking thyroid hormone receptor alpha or beta 
Organisation École normale supérieure de Lyon (ENS Lyon)
Department Laboratory of Molecular and Cellular Biology (UMR 5665 CNRS)
Country France 
Sector Academic/University 
PI Contribution We characterised the skeletal development and adult bone in TRa0/0 and TRb-/- mice and also determined heparan sulphate proteoglycan expression the growth plate in these mice.
Collaborator Contribution Generation of mice lacking all isoforms of either thyroid hormone receptor alpha (TRa0/0) or thyroid hormone receptor beta (TRb-/-). They have provided skeletal samples from these mice.
Impact Results of this collaboration are published in PMID: 17327419 PMID: 17327419
 
Description Association of multiple endocrine neoplasia dissorders (AMEND) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Session Chair and symposium speaker on current guidlines for management and treatment of familial thyroid disease.

Improved patient education
Year(s) Of Engagement Activity 2009
 
Description British Thyroid Foundation Newsletter 2006 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Report of research outcomes for studies funded by the British Thyroid Foundation Research Award 2004

Highlighted the importance of thyroid research to patient groups.
Year(s) Of Engagement Activity 2006
 
Description British Thyroid Foundation Newsletter 2008 
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 Report of research outcomes for studies funded by the British Thyroid Foundation Research Award 2007

Highlighted the importance of skeletal thyroid research to patients with thyroid disease.
Year(s) Of Engagement Activity 2008
 
Description Careers in Academic Medicine, Royal College of Physicians, London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Health professionals
Results and Impact 30 minute lecture entitled "Title: "Why undertake a cereer in Academic medicine: A personal experience"

The aim opf this meeting was to increase recruitment of junior doctors into academic medicine
Year(s) Of Engagement Activity 2006
 
Description Kings College School Wimbledon 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Meeting for prospective medical and veterinary students from Kings College Wimbledon and their parents to advice regarding university applications and future career possibilities in clinical medicine and academia

Opportunity to meet candidates prior to university interview for additional advice
Year(s) Of Engagement Activity 2015
URL https://www.kcs.org.uk/
 
Description School Visit 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Meeting of >50 school children interested in a career in Medicine and Science meeting with physicians and scientists which resulted in discussions about opportunities for studying and pursuing a scientific research career in basic and clinical areas.
Year(s) Of Engagement Activity 2015,2016
URL https://www.kcs.org.uk/content/science-medics-networking
 
Description Society for Endocrinology Task Force on Recruitment into Academic Endocrinology 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Health professionals
Results and Impact This committee advised the Society for Endocinology Executive Committee on mechanisms to improve academic recruitment to the speciality

Increased awarness of the speciality as a result of research awards and travel grants.
Year(s) Of Engagement Activity 2008