Objective
Thyroid hormone (T3) acts via thyroid hormone receptors alpha (TRa) and beta (TRb), and is essential for skeletal development and bone mineralisation. T3 excess is associated with an increased risk of osteoporotic fracture and is an important contributor to the morbid and financial burden of disease, although the role of T3 in bone formation and turnover is poorly characterised. The syndrome of resistance to thyroid hormone (RTH) is an autosomal dominant condition that results from dominant negative mutant TRb proteins. Short stature and abnormal skeletal development are prominent features in human RTH. In contrast, TRa mutations have not been described in man and are postulated to be lethal or cause no phenotype. To investigate the mechanisms of T3 action in bone, we will examine bone development in mice with an RTH mutation (PV) targeted to TRb or TRa1 by homologous recombination.
Our initial work has shown that TRbPV mice recapitulate human RTH but display skeletal thyrotoxicosis, whilst TRa1PV mice exhibit miled thyroid failure, normal circulating hormone concentrations and skeletal hypothyroidism. Thus, TRa1 and TRb PV mutant mice afford a unique opportunity to characterise T3 action in skeletal cells. In this Outgoing International Fellowship, I will work in two world-leading laboratories in the USA and UK to i) identify skeletal T3-targel genes by RNA microarray analysis and subtraction hybridisation, ii) identify T3-reponse elements in the promoter regions of target genes, iii) characterise the molecular interactions of wild-type and PV mutant TRs at target gene promoters by chromatin immunoprecipitation and iv) analyse the expression of new skeletal T3-target genes in TRa1 and TRb wild-type and mutant mice during development and in response to alterations in thyroid status. The successful achievement of these objectives is dependent on mobility outside Europe and this Fellowship will clearly strengthen and diversify EU scientific excellence.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences biochemistry biomolecules proteins
- natural sciences biological sciences genetics mutation
- natural sciences biological sciences genetics RNA
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Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Call for proposal
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Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
FP6-2002-MOBILITY-6
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Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
OIF - Marie Curie actions-Outgoing International Fellowships
Coordinator
LONDON
United Kingdom
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