title: Reward-based hypertension control by a synthetic brain-dopamine interface.
abstract: Synthetic biology has significantly advanced the design of synthetic trigger-controlled devices that can reprogram mammalian cells to interface with complex metabolic activities. In the brain, the neurotransmitter dopamine coordinates communication with target neurons via a set of dopamine receptors that control behavior associated with reward-driven learning. This dopamine transmission has recently been suggested to increase central sympathetic outflow, resulting in plasma dopamine levels that correlate with corresponding brain activities. By functionally rewiring the human dopamine receptor D1 (DRD1) via the second messenger cyclic adenosine monophosphate (cAMP) to synthetic promoters containing cAMP response element-binding protein 1(CREB1)-specific cAMP-responsive operator modules, we have designed a synthetic dopamine-sensitive transcription controller that reversibly fine-tunes specific target gene expression at physiologically relevant brain-derived plasma dopamine levels. Following implantation of circuit-transgenic human cell lines insulated by semipermeable immunoprotective microcontainers into mice, the designer device interfaced with dopamine-specific brain activities and produced a systemic expression response when the animal's reward system was stimulated by food, sexual arousal, or addictive drugs. Reward-triggered brain activities were able to remotely program peripheral therapeutic implants to produce sufficient amounts of the atrial natriuretic peptide, which reduced the blood pressure of hypertensive mice to the normal physiologic range. Seamless control of therapeutic transgenes by subconscious behavior may provide opportunities for treatment strategies of the future.
authors.affiliation: Department of Biosystems Science and Engineering, Eidgenössiche Technische Hochschule Zurich, CH-4058 Basel, Switzerland.
authors.forename: Katrin
authors.initials: K
authors.lastname: Rössger
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Charpin-El Hamri
authors.forename: Martin
authors.initials: M
authors.lastname: Fussenegger
mesh_terms: D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D004298:Dopamine / Q000097:blood* / Q000494:pharmacology; D004337:Drug Carriers / Q000008:administration & dosage*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005818:Genetic Engineering / Q000379:methods*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D051379:Mice; D008991:Monitoring, Physiologic / Q000379:methods; D017447:Receptors, Dopamine D1 / Q000235:genetics; D012201:Reward
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004337:Drug Carriers; D017447:Receptors, Dopamine D1; D000242:Cyclic AMP; D004298:Dopamine
keywords: designer cells; gene regulation; gene switch; prosthetic networks; synthetic gene circuits