Disorders of Thyroid Hormone Action: Diagnosis, Pathophysiology and Therapy (360G-Wellcome-210755_Z_18_Z)

Having discovered that cystic degeneration of aortic media in human selenoprotein deficiency causes its aneurysmal dilatation, we will elucidate its pathogenesis using mice with conditional, aortic selenoprotein depletion and patients stem cell-derived vascular smooth muscle cells and determine whether antioxidants can inhibit this process. We will investigate structure-function relationships in SECISBP2, including how deficiency of this master regulator is variably rate-limiting for synthesis of different selenoproteins. Following our first identification of RTHalpha, a disorder due to TRalpha mutations with tissue-selective hypothyroidism but near-normal thyroid hormone levels, we will determine its genetic architecture and phenotypic spectrum. We will identify abnormalities in circulating metabolites and proteins to enable diagnosis of RTHalpha and guide its therapy. Aided by structural insights, we will design and test thyroid hormone analogues that disrupt mutant TRalpha-corepressor interaction, the basis of dominant negative inhibition which mediates pathogenesis of the disorder. We will develop biochemical markers to differentially diagnose RTHbeta cases from patients with TSH-secreting tumours and to guide RTHbeta therapy. In patients with deficiency of the MCT8 thyroid hormone transporter, we will trial whether treatment with triiodothyroacetic acid, a thyroid hormone analogue whose cellular transport is MCT8-independent, alters neurodevelopmental outcome.