Synthetic gene network restoring endogenous pituitary-thyroid feedback control in experimental Graves' disease
Synthetic gene network restoring endogenous pituitary-thyroid feedback control in experimental Graves' disease
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DOI：
10.1073/pnas.1514383113
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发表时间：
2016-02-02
影响因子：
11.1
通讯作者：
Fussenegger，Martin
中科院分区：
文献类型：
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作者：
Saxena，Pratik;Charpin-El Hamri，Ghislaine;Fussenegger，Martin
Graves病是一种自身免疫性疾病，由于自身抗体与甲状腺上的促甲状腺激素受体（TSHR）结合，触发甲状腺激素释放，导致甲状腺功能亢进。这些刺激性自身抗体破坏了通过下丘脑-垂体-甲状腺轴反馈回路对甲状腺激素稳态的生理控制。为了重置内源性促甲状腺激素反馈控制，我们设计了一个合成的哺乳动物基因电路，通过监测甲状腺激素水平和协调促甲状腺激素受体拮抗剂（TSHAntag）的表达来维持甲状腺激素稳态，该拮抗剂竞争性抑制促甲状腺激素或人类自身抗体与TSHR的结合。该合成控制装置由合成甲状腺敏感受体（TSR）、酵母Gal 4蛋白/人甲状腺受体-α融合体组成，其可逆地触发TSR依赖性启动子的TSH拮抗基因表达。在甲状腺功能亢进的小鼠中，这种合成回路感知到病理性甲状腺激素水平，并将下丘脑-垂体-甲状腺轴的促甲状腺反馈控制恢复到正常甲状腺激素水平。治疗性即插即用基因电路恢复代谢紊乱的生理反馈控制，促进先进的基于基因和细胞的治疗。
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 TSHAntaggene 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 circuits that restore physiological feedback control in metabolic disorders foster advanced gene- and cell-based therapies.