Project description:Striatum in rich in GABAergic neurons which require thyroid hormone for their maturation. We used propyl thio uracyl to make mice hypothyroid, and then restored the hormonal level using thyroid hormone. This provided 3 groups of mice for striatum RNAseq analysis. Our results point to GABAergic neurons as direct targets of thyroid hormone during brain development and suggest that many defects seen in hypothyroid brains may be secondary to GABAergic neuron malfunction.
Project description:Background: Sex and age have substantial influence on thyroid function. Sex influences the risk and clinical expression of thyroid disorders (TDs), with age a proposed trigger for the development of TDs. Cardiac function is affected by thyroid hormone levels with gender differences. Accordingly, we investigated the proteomic changes involved in sex based cardiac responses to thyroid dysfunction in elderly mice. Methods: Aged (18-20 months) male and female C57BL/6 mice were fed diets to create euthyroid, hypothyroid, or hyperthyroid states. Serial echocardiographs were performed to assess heart function. Proteomic changes in cardiac protein profiles were assessed by 2-D DIGE and LC-MS/MS, and a subset confirmed by immunoblotting. Results: Serial echocardiographs showed ventricular function remained unchanged regardless of treatment. Heart rate and size increased (hyperthyroid) or decreased (hypothyroid) independent of sex. Pairwise comparison between the six groups identified 55 proteins (≥ 1.5-fold difference and p < 0.1). Compared to same-sex controls 26/55 protein changes were in the female hypothyroid heart, whereas 15/55 protein changes were identified in the male hypothyroid, and male and female hyperthyroid heart. The proteins mapped to oxidative phosphorylation, tissue remodeling and inflammatory response pathways. Conclusion: We identified both predicted and novel proteins with gender specific differential expression in response to thyroid hormone status, providing a catalogue of proteins associated with thyroid dysfunction. Pursuit of these proteins and their involvement in cardiac function will expand our understanding of mechanisms involved in sex-based cardiac response to thyroid dysfunction.
Project description:We investigated the effects of thyroid hormone disruptions on gene expression in juvenile mice liver to develop a stronger understanding of the mechanisms by which thyroid disrupting chemicals impair development. Gene expression was examined by hybridization of hepatic RNA to Agilent mouse microarrays for hyper-, hypo-, hypo-replacement (hypo+) and euthyroid animals. Keywords: Toxicogenomics, biomarkers of thyroid disruptors Hypothyroidism was induced from post natal day (PND) 13 to 15 by adding model thyroid toxicants methimazole and sodium perchlorate to drinking water of pregnant females. Hyperthyroidism was induced by intraperitoneal injections (i.p.) of THs at PND 15, 4 hours before decapitation and tissue collection. For the hypothyroid/replacement group; dams were provided with drinking water for 3 days (PND 13 to 15), containing a mixture of methimazole/sodium perchlorate. Pups then received intraperitoneal injections of thyoid hormones on PND 15, 4 hours before decapitation and tissue collection.
Project description:We ablated the expression of the Nuclear Receptor Corepressor 1 specifically in mice livers and rendered them hypothyroid. Then we performed H3K27 acetylation CHIP-Seq. We found decreased H3K27ac in the livers of hypothyroid wild type and NCoR1KO mice. Therefore, we concluded that the thyroid hormone receptor may recruit histone deacetilases independently of NCoR1.
Project description:The function of the thyroid gland is to metabolize iodide to synthesize hormones that act on almost all tissues and are essential for normal growth and metabolism. Low plasma levels of thyroid hormones lead to hypothyroidism, which is one of the most common diseases in the general population and cannot be always satisfactorily treated by lifelong hormone replacement. Therefore, in addition to the lack of in vitro tractable models to study human thyroid development, differentiation and maturation, there is a need for new therapeutic approaches that involve replacement of thyroid tissue to better control hormone balance. Here we report the first model of thyroid organoids derived from human embryonic stem cells that produce thyroid hormones in vitro and are capable of restoring plasma thyroid hormone levels when transplanted into athyreotic mice.
Project description:The function of the thyroid gland is to metabolize iodide to synthesize hormones that act on almost all tissues and are essential for normal growth and metabolism. Low plasma levels of thyroid hormones lead to hypothyroidism, which is one of the most common diseases in the general population and cannot be always satisfactorily treated by lifelong hormone replacement. Therefore, in addition to the lack of in vitro tractable models to study human thyroid development, differentiation and maturation, there is a need for new therapeutic approaches that involve replacement of thyroid tissue to better control hormone balance. Here we report the first model of thyroid organoids derived from human embryonic stem cells that produce thyroid hormones in vitro and are capable of restoring plasma thyroid hormone levels when transplanted into athyreotic mice.
Project description:The function of the thyroid gland is to metabolize iodide to synthesize hormones that act on almost all tissues and are essential for normal growth and metabolism. Low plasma levels of thyroid hormones lead to hypothyroidism, which is one of the most common diseases in the general population and cannot be always satisfactorily treated by lifelong hormone replacement. Therefore, in addition to the lack of in vitro tractable models to study human thyroid development, differentiation and maturation, there is a need for new therapeutic approaches that involve replacement of thyroid tissue to better control hormone balance. Here we report the first model of thyroid organoids derived from human embryonic stem cells that produce thyroid hormones in vitro and are capable of restoring plasma thyroid hormone levels when transplanted into athyreotic mice.
Project description:The function of the thyroid gland is to metabolize iodide to synthesize hormones that act on almost all tissues and are essential for normal growth and metabolism. Low plasma levels of thyroid hormones lead to hypothyroidism, which is one of the most common diseases in the general population and cannot be always satisfactorily treated by lifelong hormone replacement. Therefore, in addition to the lack of in vitro tractable models to study human thyroid development, differentiation and maturation, there is a need for new therapeutic approaches that involve replacement of thyroid tissue to better control hormone balance. Here we report the first model of thyroid organoids derived from human embryonic stem cells that produce thyroid hormones in vitro and are capable of restoring plasma thyroid hormone levels when transplanted into athyreotic mice.
Project description:We used microarrays to investigate differential gene expression in different thyroid hormone receptor beta mouse models. Hypothyroid wild type, TRbeta KO and TRbeta GS mutant mice were treated with T3 or vehicle alone. Microarray analysis revealed that the gene expression pattern in TRbeta GS mutant mice was similar to that in TRbeta KO mice.
Project description:Thyroid hormone (3,5,3'-triiodothyronine, T3) sensitively influences the pituitary gland, a source of hormones that control tissues throughout the body. The underlying transcriptional response is believed to hinge crucially on interaction of T3 receptors with enhancers in the genome but it remains unknown how T3 regulates pituitary chromatin and how this regulation adjusts to hypothyroid and hyperthyroid conditions.