Synthetic gene network restoring endogenous pituitary-thyroid feedback control in experimental Graves' disease

Proceedings of the National Academy of Sciences of the United States of America
Pratik SaxenaMartin Fussenegger

Abstract

Graves' disease is an autoimmune disorder that causes hyperthyroidism because of autoantibodies that bind to the thyroid-stimulating hormone receptor (TSHR) on the thyroid gland, triggering thyroid hormone release. The physiological control of thyroid hormone homeostasis by the feedback loops involving the hypothalamus-pituitary-thyroid axis is disrupted by these stimulating autoantibodies. To reset the endogenous thyrotrophic feedback control, we designed a synthetic mammalian gene circuit that maintains thyroid hormone homeostasis by monitoring thyroid hormone levels and coordinating the expression of a thyroid-stimulating hormone receptor antagonist (TSHAntag), which competitively inhibits the binding of thyroid-stimulating hormone or the human autoantibody to TSHR. This synthetic control device consists of a synthetic thyroid-sensing receptor (TSR), a yeast Gal4 protein/human thyroid receptor-α fusion, which reversibly triggers expression of the TSHAntag gene from TSR-dependent promoters. In hyperthyroid mice, this synthetic circuit sensed pathological thyroid hormone levels and restored the thyrotrophic feedback control of the hypothalamus-pituitary-thyroid axis to euthyroid hormone levels. Therapeutic plug and play gene c...Continue Reading

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Citations

Apr 14, 2016·Journal of Hepatology·Peng BaiMartin Fussenegger
May 30, 2016·Current Opinion in Chemical Biology·Daniel Bojar, Martin Fussenegger
Jun 25, 2016·Wiley Interdisciplinary Reviews. Systems Biology and Medicine·Lina Schukur, Martin Fussenegger
Jan 17, 2017·Nature Chemical Biology·Marius MüllerMartin Fussenegger
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Dec 13, 2016·Angewandte Chemie·Simon AusländerMartin Fussenegger
Sep 17, 2018·Nucleic Acids Research·Ying LiuMartin Fussenegger
Oct 21, 2018·Proceedings of the National Academy of Sciences of the United States of America·Daniel A CharleboisGábor Balázsi
May 19, 2020·Nucleic Acids Research·Pascal StücheliMartin Fussenegger
May 20, 2016·Cold Spring Harbor Perspectives in Biology·Simon Ausländer, Martin Fussenegger
May 18, 2018·Nature Communications·Yasunori OkamotoThomas R Ward
Mar 19, 2020·Cellular and Molecular Life Sciences : CMLS·Ryosuke KojimaMartin Fussenegger
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May 10, 2018·Nature Communications·Ferdinand SedlmayerMartin Fussenegger
Sep 1, 2017·Porto Biomedical Journal·Fanny Michel, Marc Folcher
Jun 21, 2018·Nature Communications·Daniel BojarMartin Fussenegger
Apr 24, 2019·Nature Biomedical Engineering·Ferdinand SedlmayerMartin Fussenegger
Jun 3, 2018·Nature Reviews. Molecular Cell Biology·Mingqi Xie, Martin Fussenegger
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Apr 25, 2018·Nature Chemical Biology·Leo SchellerMartin Fussenegger
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Apr 6, 2021·Synthetic Biology·Mingqi XieMartin Fussenegger
May 18, 2021·Frontiers in Bioengineering and Biotechnology·Jing LiWenlin An
Oct 8, 2021·Nature Reviews. Drug Discovery·Andres Cubillos-RuizJose M Lora

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