The long-term objective of this project is to understand the molecular mechanisms of thyroid hormone action. Thyroid hormone is an important regulator of development and homeostasis, and abnormalities in thyroid status correlate with many human diseases ranging from cancer to birth defects to metabolic disorders. Thyroxine (T4) is the major form of thyroid hormone that is secreted from the thyroid gland, and T4 is metabolized to the active hormone T3 by enzymatic deiodination. T3 regulates the transcription of thyroid hormone responsive genes by binding to and activating nuclear thyroid hormone receptors. However, there are many effects of thyroid hormone that occur much faster than the timescale of transcriptional regulation, and the molecular mechanisms of these rapid effects are unknown. This research plan is constructed around the hypothesis that rapid thyroid hormone signaling involves a novel metabolite of T4 that is chemically distinct from T3. This hypothesis is supported by experiments showing the existence of this novel metabolite in tissue, as well as the induction of rapid physiological responses when the metabolite is administered in vivo. In addition, this T4 metabolite is a potent agonist of a newly discovered orphan G protein-coupled receptor (GPCR) related to the family of a biogenic amine GPCRs. This research plan seeks to further explore this novel pathway of thyroid hormone signaling.
Specific aim 1 involves chemical modification of the metabolite to delineate the structural features important to GPCR activation.
Specific aim 2 is a study to understand the enzymology responsible for generating the rapid-acting T4 metabolite.
Specific aim 3 involves the isolation, expression, and pharmacological characterization of the different subtypes of the GPCR that responds to the metabolite.
Specific aim 4 is an approach to examine different tissues for the presence of the metabolite and perform quantitative analysis.
Specific aim 5 is a plan to develop a chemical antagonist of the metabolite that will be useful for studying the in vivo biology of this new thyroid hormone signaling pathway.
| Aguayo-Mazzucato, Cristina; Lee Jr, Terence B; Matzko, Michelle et al. (2018) T3 Induces Both Markers of Maturation and Aging in Pancreatic ?-Cells. Diabetes 67:1322-1331 |
| Yu, Guoying; Tzouvelekis, Argyris; Wang, Rong et al. (2018) Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function. Nat Med 24:39-49 |
| Ferrara, Skylar J; Bourdette, Dennis; Scanlan, Thomas S (2018) Hypothalamic-Pituitary-Thyroid Axis Perturbations in Male Mice by CNS-Penetrating Thyromimetics. Endocrinology 159:2733-2740 |
| Bárez-López, Soledad; Hartley, Meredith D; Grijota-Martínez, Carmen et al. (2018) Sobetirome and its Amide Prodrug Sob-AM2 Exert Thyromimetic Actions in Mct8-Deficient Brain. Thyroid 28:1211-1220 |
| Devereaux, Jordan; Ferrara, Skylar J; Scanlan, Thomas S (2018) Quantification of Thyromimetic Sobetirome Concentration in Biological Tissue Samples. Methods Mol Biol 1801:193-206 |
| Meinig, J Matthew; Ferrara, Skylar J; Banerji, Tania et al. (2017) Targeting Fatty-Acid Amide Hydrolase with Prodrugs for CNS-Selective Therapy. ACS Chem Neurosci 8:2468-2476 |
| Ma, Hongwei; Yang, Fan; Butler, Michael R et al. (2017) Inhibition of thyroid hormone receptor locally in the retina is a therapeutic strategy for retinal degeneration. FASEB J 31:3425-3438 |
| Hartley, Meredith D; Kirkemo, Lisa L; Banerji, Tapasree et al. (2017) A Thyroid Hormone-Based Strategy for Correcting the Biochemical Abnormality in X-Linked Adrenoleukodystrophy. Endocrinology 158:1328-1338 |
| Ferrara, Skylar J; Meinig, J Matthew; Placzek, Andrew T et al. (2017) Ester-to-amide rearrangement of ethanolamine-derived prodrugs of sobetirome with increased blood-brain barrier penetration. Bioorg Med Chem 25:2743-2753 |
| Placzek, Andrew T; Ferrara, Skylar J; Hartley, Meredith D et al. (2016) Sobetirome prodrug esters with enhanced blood-brain barrier permeability. Bioorg Med Chem 24:5842-5854 |
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