TRActionProject reference: 330183
Funded under :
Molecular pathogenesis of a novel thyroid hormone resistance syndrome caused by mutations in thyroid receptor alpha 1
Total cost:EUR 115 641,6
EU contribution:EUR 115 641,6
Coordinated in:United Kingdom
Topic(s):FP7-PEOPLE-2012-IEF - Marie-Curie Action: "Intra-European fellowships for career development"
Call for proposal:FP7-PEOPLE-2012-IEFSee other projects for this call
Funding scheme:MC-IEF - Intra-European Fellowships (IEF)
Thyroid hormone (TH) is crucial for the normal development and metabolism of all tissues. The actions of the bioactive T3 are mediated by binding to its nuclear receptors (TRs), of which TRa1 and TRb1 are the main isoforms. It is known for decades that mutations in TRb1 result in resistance to TH, among others characterized by goiter and tachycardia, and abnormal TH levels.
Ever since its characterization in 1987, investigators have searched for patients with mutations in TRa1. However, very recently the host and applicant’s laboratory independently discovered the first patients with inactivating mutations in TRa1. These patients show growth retardation, delayed bone, motor and mental development as well as abnormal TH levels.
The patients display remarkable differences in neurological, bone and biochemical phenotype. Interestingly, all mutants are located within exon 9, which encodes a domain important for ligand binding and interaction with co-activator and co-repressor proteins. It is likely that mutant-specific properties underlie the differences in clinical phenotype.
The aim of this project is to unravel the molecular mechanisms leading to the clinical phenotype of patients with TRa1 mutations. The key objectives are: (i) to study direct effects of mutations in a reporter assay; (ii) to detail consequences of mutations on downstream target genes; (iii) to identify alterations in the interaction of the receptor mutants with cofactor proteins and (iv) to establish a genotype-phenotype relationship.
Using an integrative approach with well-established and advanced techniques, this scientifically fascinating project will certainly deepen our understanding of the role of TRa1 in health and disease.
The combination of the longstanding expertise of resistance to TH in the host laboratory together with my studies and experience concerning all aspects of cellular TH regulation will promise the success of this project.
EU contribution: EUR 115 641,6
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