The broad objective of this research proposal is to advance understanding of thyroid physiology through study of genetic defects at key regulatory processes. In addition to identification of new syndromes and gene defects, research centers on the mediation of thyroid hormone (TH) effects by studying syndromes of reduced sensitivity to TH due to defects in cell membrane transport, metabolism and action. These are caused, respectively, by mutations in the MCT8 (monocarboxylate transporter 8), SBP2 (selenocysteine insertion sequence-binding protein 2) and TRIl (nuclear TH receptor IJ) genes and others not yet identified. Each is studied by a triple approach, clinical (in vivo), tissue and gene expression (in-vitro) and animal models (gene altered mice that recapitulate the defect in humans). Each approach complements the other and compensates for their inherent limitations. 1. Clinical studies will serve to better characterize the phenotype, to identify tissue and organ specific defects in TH transport and metabolism. Studies will include prenatal genotyping and attempted treatment. New variants and unusual phenotypes will be sought. 2. In vitro studies using primary culture of the patients' skin fibroblasts and heterologous expression of the defective genes will serve to determine the properties of the defective molecules in isolation. In the case of SBP2 defects, in vitro studies will serve to determine the effects of various mutations on gene transcription and translation. Examination of patients' tissues by immunohistochemistry, will serve to identify the consequences of the defects at the cell level and to verify the pertinence of results generated from animal experiment. 3. Mice deficient in the substances being studied and those harboring the mutations observed in humans, will allow for better characterization of the defects under investigation and for the testing of various modalities of potential treatment. Mice deficient in the Mct8 gene have proven invaluable in the understanding of the thyroid abnormalities in humans and will now serve to characterize the consequences of Mct8 deficiency in embryonic and early postpartum life and the potentials of prenatal therapeutic intervention. The creation of inducible Sbp2K0 mice will facilitate determination of the timing of expression of selenoproteins that are crucial to survival and development, as well as the consequences of their deficiency. Massively-parallel sequencing will be applied for the identification of the gene(s) involved in resistance to TH not linked to the TRIi gene. Thus, function of such new genes will be characterized.
The study of newlly identified congenital and inherited diseases provides not only insight into thyroid physiology but also establishes chriteria for their diagnosis, screening, and genetic counseling. Identification of mutations in women carriers of MCT8 defects allow for the provision of prenatal diagnosis particularly important since these defects produce incapacitating illness in male offspring. This also applies to the more severe forms of SBP2 and TRB gene defects. The proposed translational approach of investigation will continue to advance the clinical knowledge as well as basic consepts of inherited desease processes.
|Bellelli, Roberto; Vitagliano, Donata; Federico, Giorgia et al. (2018) Oncogene-induced senescence and its evasion in a mouse model of thyroid neoplasia. Mol Cell Endocrinol 460:24-35|
|Cangul, Hakan; Liao, Xiao-Hui; Schoenmakers, Erik et al. (2018) Homozygous loss-of-function mutations in SLC26A7 cause goitrous congenital hypothyroidism. JCI Insight 3:|
|Watanabe, Y; Sharwood, E; Goodwin, B et al. (2018) A novel mutation in the TG gene (G2322S) causing congenital hypothyroidism in a Sudanese family: a case report. BMC Med Genet 19:69|
|Ohba, Kenji; Sinha, Rohit Anthony; Singh, Brijesh Kumar et al. (2017) Changes in Hepatic TR? Protein Expression, Lipogenic Gene Expression, and Long-Chain Acylcarnitine Levels During Chronic Hyperthyroidism and Triiodothyronine Withdrawal in a Mouse Model. Thyroid 27:852-860|
|Hönes, G Sebastian; Rakov, Helena; Logan, John et al. (2017) Noncanonical thyroid hormone signaling mediates cardiometabolic effects in vivo. Proc Natl Acad Sci U S A 114:E11323-E11332|
|Srichomkwun, Panudda; Anselmo, João; Liao, Xiao-Hui et al. (2017) Fetal Exposure to High Maternal Thyroid Hormone Levels Causes Central Resistance to Thyroid Hormone in Adult Humans and Mice. J Clin Endocrinol Metab 102:3234-3240|
|Grasberger, Helmut; Refetoff, Samuel (2017) Resistance to thyrotropin. Best Pract Res Clin Endocrinol Metab 31:183-194|
|Pappa, Theodora; Moeller, Lars C; Edidin, Deborah V et al. (2017) A Novel Mutation in the TBG Gene Producing Partial Thyroxine-Binding Globulin Deficiency (Glencoe) Identified in 2 Families. Eur Thyroid J 6:138-142|
|Turgeon, Marc-Olivier; Silander, Tanya L; Doycheva, Denica et al. (2017) TRH Action Is Impaired in Pituitaries of Male IGSF1-Deficient Mice. Endocrinology 158:815-830|
|Srichomkwun, Panudda; Scherberg, Neal H; Jakši?, Jasminka et al. (2017) Diagnostic Dilemma in Discordant Thyroid Function Tests Due to Thyroid Hormone Autoantibodies. AACE Clin Case Rep 3:e22-e25|
Showing the most recent 10 out of 230 publications