Source 1primary paper2012Proceedings of the National Academy of Sciences
Toolkit/chimeric trace-amine-associated receptor 1
chimeric trace-amine-associated receptor 1
Also known as: cTAAR1
Taxonomy: Mechanism Branch / Architecture. Workflows sit above the mechanism and technique branches rather than replacing them.
Summary
Chimeric trace-amine-associated receptor 1 (cTAAR1) is a synthetic rewired receptor module that converts guanabenz input into cAMP/PKA-dependent CREB1 activation and transcription from promoters containing CREB1-specific cAMP response elements. In the reported designer circuit, this control system regulated expression of a GLP-1-Fc(mIgG)-Leptin payload.
Usefulness & Problems
Why this is useful
cTAAR1 is useful as a pharmacologically controlled gene-regulation module that links a small-molecule input to programmable transcriptional output. The reported system enabled guanabenz-dependent control of a therapeutic transgene cassette and supported regulated secretion of GLP-1 and leptin in a metabolic syndrome application.
Source:
In mice developing symptoms of the metabolic syndrome, this three-in-one treatment strategy was able to simultaneously attenuate hypertension and hyperglycemia as well as obesity and dyslipidemia
Problem solved
This construct addresses the problem of externally controlling therapeutic gene expression with a defined small-molecule trigger. Specifically, it provides a rewired receptor-to-transcription pathway in which guanabenz drives CREB1-responsive promoter activation and dose-dependent expression of GLP-1-Fc(mIgG)-Leptin.
Source:
In mice developing symptoms of the metabolic syndrome, this three-in-one treatment strategy was able to simultaneously attenuate hypertension and hyperglycemia as well as obesity and dyslipidemia
Problem links
Need conditional control of signaling activity
DerivedChimeric trace-amine-associated receptor 1 (cTAAR1) is a synthetic rewired receptor module that converts guanabenz input into cAMP/PKA-dependent CREB1 activation and transcription from promoters containing CREB1-specific cAMP response elements. In the reported designer circuit, this control system regulated expression of a GLP-1-Fc(mIgG)-Leptin payload.
Need conditional recombination or state switching
DerivedChimeric trace-amine-associated receptor 1 (cTAAR1) is a synthetic rewired receptor module that converts guanabenz input into cAMP/PKA-dependent CREB1 activation and transcription from promoters containing CREB1-specific cAMP response elements. In the reported designer circuit, this control system regulated expression of a GLP-1-Fc(mIgG)-Leptin payload.
Need tighter control over gene expression timing or amplitude
DerivedChimeric trace-amine-associated receptor 1 (cTAAR1) is a synthetic rewired receptor module that converts guanabenz input into cAMP/PKA-dependent CREB1 activation and transcription from promoters containing CREB1-specific cAMP response elements. In the reported designer circuit, this control system regulated expression of a GLP-1-Fc(mIgG)-Leptin payload.
Taxonomy & Function
Primary hierarchy
Mechanism Branch
Architecture: A reusable architecture pattern for arranging parts into an engineered system.
Mechanisms
camp/pka-mediated creb1 activationsignal transduction rewiringsmall-molecule receptor activation by guanabenztranscriptional activation from creb1-specific camp response elementsTechniques
No technique tags yet.
Target processes
recombinationsignalingtranscriptionImplementation Constraints
cofactor dependency: cofactor requirement unknownencoding mode: genetically encodedimplementation constraint: context specific validationimplementation constraint: payload burdenoperating role: regulator
The reported design rewired cTAAR1 signaling through a cAMP/PKA-mediated CREB1 pathway to drive transcription from synthetic promoters containing CREB1-specific cAMP response elements. In the described application, this transcriptional output controlled a GLP-1-Fc(mIgG)-Leptin expression cassette, and guanabenz served as the activating small molecule.
The available evidence is limited to a single cited study and provides little detail here on receptor architecture, quantitative dynamic range, background activity, or off-target signaling. Independent replication, broader cross-context validation, and implementation performance in other cell types or payloads are not documented in the supplied evidence.
Validation
Cell-freeBacteriaMammalianMouseHumanTherapeuticIndep. Replication
Supporting Sources
Ranked Claims
Guanabenz activates a synthetic signal cascade that stimulates secretion of GLP-1 and leptin.
the clinically licensed antihypertensive drug guanabenz (Wytensin) activates a synthetic signal cascade that stimulates the secretion of metabolically active peptides GLP-1 and leptin
Guanabenz activates a synthetic signal cascade that stimulates secretion of GLP-1 and leptin.
the clinically licensed antihypertensive drug guanabenz (Wytensin) activates a synthetic signal cascade that stimulates the secretion of metabolically active peptides GLP-1 and leptin
Guanabenz activates a synthetic signal cascade that stimulates secretion of GLP-1 and leptin.
the clinically licensed antihypertensive drug guanabenz (Wytensin) activates a synthetic signal cascade that stimulates the secretion of metabolically active peptides GLP-1 and leptin
Guanabenz activates a synthetic signal cascade that stimulates secretion of GLP-1 and leptin.
the clinically licensed antihypertensive drug guanabenz (Wytensin) activates a synthetic signal cascade that stimulates the secretion of metabolically active peptides GLP-1 and leptin
Guanabenz activates a synthetic signal cascade that stimulates secretion of GLP-1 and leptin.
the clinically licensed antihypertensive drug guanabenz (Wytensin) activates a synthetic signal cascade that stimulates the secretion of metabolically active peptides GLP-1 and leptin
Guanabenz activates a synthetic signal cascade that stimulates secretion of GLP-1 and leptin.
the clinically licensed antihypertensive drug guanabenz (Wytensin) activates a synthetic signal cascade that stimulates the secretion of metabolically active peptides GLP-1 and leptin
Guanabenz activates a synthetic signal cascade that stimulates secretion of GLP-1 and leptin.
the clinically licensed antihypertensive drug guanabenz (Wytensin) activates a synthetic signal cascade that stimulates the secretion of metabolically active peptides GLP-1 and leptin
Guanabenz dose-dependently controls expression of GLP-1-Fc(mIgG)-Leptin.
it was possible to use guanabenz to dose-dependently control expression of GLP-1-Fc(mIgG)-Leptin
Guanabenz dose-dependently controls expression of GLP-1-Fc(mIgG)-Leptin.
it was possible to use guanabenz to dose-dependently control expression of GLP-1-Fc(mIgG)-Leptin
Guanabenz dose-dependently controls expression of GLP-1-Fc(mIgG)-Leptin.
it was possible to use guanabenz to dose-dependently control expression of GLP-1-Fc(mIgG)-Leptin
Guanabenz dose-dependently controls expression of GLP-1-Fc(mIgG)-Leptin.
it was possible to use guanabenz to dose-dependently control expression of GLP-1-Fc(mIgG)-Leptin
Guanabenz dose-dependently controls expression of GLP-1-Fc(mIgG)-Leptin.
it was possible to use guanabenz to dose-dependently control expression of GLP-1-Fc(mIgG)-Leptin
Guanabenz dose-dependently controls expression of GLP-1-Fc(mIgG)-Leptin.
it was possible to use guanabenz to dose-dependently control expression of GLP-1-Fc(mIgG)-Leptin
Guanabenz dose-dependently controls expression of GLP-1-Fc(mIgG)-Leptin.
it was possible to use guanabenz to dose-dependently control expression of GLP-1-Fc(mIgG)-Leptin
Signal transduction of cTAAR1 was functionally rewired through cAMP/PKA-mediated activation of CREB1 to drive transcription from synthetic promoters containing CREB1-specific cAMP response elements.
the signal transduction of a chimeric trace-amine-associated receptor 1 (cTAAR1) was functionally rewired via cAMP and cAMP-dependent phosphokinase A (PKA)-mediated activation of the cAMP-response element binding protein (CREB1) to transcription of synthetic promoters containing CREB1-specific cAMP response elements
Signal transduction of cTAAR1 was functionally rewired through cAMP/PKA-mediated activation of CREB1 to drive transcription from synthetic promoters containing CREB1-specific cAMP response elements.
the signal transduction of a chimeric trace-amine-associated receptor 1 (cTAAR1) was functionally rewired via cAMP and cAMP-dependent phosphokinase A (PKA)-mediated activation of the cAMP-response element binding protein (CREB1) to transcription of synthetic promoters containing CREB1-specific cAMP response elements
Signal transduction of cTAAR1 was functionally rewired through cAMP/PKA-mediated activation of CREB1 to drive transcription from synthetic promoters containing CREB1-specific cAMP response elements.
the signal transduction of a chimeric trace-amine-associated receptor 1 (cTAAR1) was functionally rewired via cAMP and cAMP-dependent phosphokinase A (PKA)-mediated activation of the cAMP-response element binding protein (CREB1) to transcription of synthetic promoters containing CREB1-specific cAMP response elements
Signal transduction of cTAAR1 was functionally rewired through cAMP/PKA-mediated activation of CREB1 to drive transcription from synthetic promoters containing CREB1-specific cAMP response elements.
the signal transduction of a chimeric trace-amine-associated receptor 1 (cTAAR1) was functionally rewired via cAMP and cAMP-dependent phosphokinase A (PKA)-mediated activation of the cAMP-response element binding protein (CREB1) to transcription of synthetic promoters containing CREB1-specific cAMP response elements
Signal transduction of cTAAR1 was functionally rewired through cAMP/PKA-mediated activation of CREB1 to drive transcription from synthetic promoters containing CREB1-specific cAMP response elements.
the signal transduction of a chimeric trace-amine-associated receptor 1 (cTAAR1) was functionally rewired via cAMP and cAMP-dependent phosphokinase A (PKA)-mediated activation of the cAMP-response element binding protein (CREB1) to transcription of synthetic promoters containing CREB1-specific cAMP response elements
Signal transduction of cTAAR1 was functionally rewired through cAMP/PKA-mediated activation of CREB1 to drive transcription from synthetic promoters containing CREB1-specific cAMP response elements.
the signal transduction of a chimeric trace-amine-associated receptor 1 (cTAAR1) was functionally rewired via cAMP and cAMP-dependent phosphokinase A (PKA)-mediated activation of the cAMP-response element binding protein (CREB1) to transcription of synthetic promoters containing CREB1-specific cAMP response elements
Signal transduction of cTAAR1 was functionally rewired through cAMP/PKA-mediated activation of CREB1 to drive transcription from synthetic promoters containing CREB1-specific cAMP response elements.
the signal transduction of a chimeric trace-amine-associated receptor 1 (cTAAR1) was functionally rewired via cAMP and cAMP-dependent phosphokinase A (PKA)-mediated activation of the cAMP-response element binding protein (CREB1) to transcription of synthetic promoters containing CREB1-specific cAMP response elements
In mice developing symptoms of metabolic syndrome, the three-in-one treatment strategy simultaneously attenuated hypertension, hyperglycemia, obesity, and dyslipidemia.
In mice developing symptoms of the metabolic syndrome, this three-in-one treatment strategy was able to simultaneously attenuate hypertension and hyperglycemia as well as obesity and dyslipidemia
In mice developing symptoms of metabolic syndrome, the three-in-one treatment strategy simultaneously attenuated hypertension, hyperglycemia, obesity, and dyslipidemia.
In mice developing symptoms of the metabolic syndrome, this three-in-one treatment strategy was able to simultaneously attenuate hypertension and hyperglycemia as well as obesity and dyslipidemia
In mice developing symptoms of metabolic syndrome, the three-in-one treatment strategy simultaneously attenuated hypertension, hyperglycemia, obesity, and dyslipidemia.
In mice developing symptoms of the metabolic syndrome, this three-in-one treatment strategy was able to simultaneously attenuate hypertension and hyperglycemia as well as obesity and dyslipidemia
In mice developing symptoms of metabolic syndrome, the three-in-one treatment strategy simultaneously attenuated hypertension, hyperglycemia, obesity, and dyslipidemia.
In mice developing symptoms of the metabolic syndrome, this three-in-one treatment strategy was able to simultaneously attenuate hypertension and hyperglycemia as well as obesity and dyslipidemia
In mice developing symptoms of metabolic syndrome, the three-in-one treatment strategy simultaneously attenuated hypertension, hyperglycemia, obesity, and dyslipidemia.
In mice developing symptoms of the metabolic syndrome, this three-in-one treatment strategy was able to simultaneously attenuate hypertension and hyperglycemia as well as obesity and dyslipidemia
In mice developing symptoms of metabolic syndrome, the three-in-one treatment strategy simultaneously attenuated hypertension, hyperglycemia, obesity, and dyslipidemia.
In mice developing symptoms of the metabolic syndrome, this three-in-one treatment strategy was able to simultaneously attenuate hypertension and hyperglycemia as well as obesity and dyslipidemia
In mice developing symptoms of metabolic syndrome, the three-in-one treatment strategy simultaneously attenuated hypertension, hyperglycemia, obesity, and dyslipidemia.
In mice developing symptoms of the metabolic syndrome, this three-in-one treatment strategy was able to simultaneously attenuate hypertension and hyperglycemia as well as obesity and dyslipidemia
Approval Evidence
1 source1 linked approval claimfirst-pass slug chimeric-trace-amine-associated-receptor-1
the signal transduction of a chimeric trace-amine-associated receptor 1 (cTAAR1) was functionally rewired
Source:
mechanistic designsupports
Signal transduction of cTAAR1 was functionally rewired through cAMP/PKA-mediated activation of CREB1 to drive transcription from synthetic promoters containing CREB1-specific cAMP response elements.
the signal transduction of a chimeric trace-amine-associated receptor 1 (cTAAR1) was functionally rewired via cAMP and cAMP-dependent phosphokinase A (PKA)-mediated activation of the cAMP-response element binding protein (CREB1) to transcription of synthetic promoters containing CREB1-specific cAMP response elements
Source:
Comparisons
Source-backed strengths
The source literature reports that guanabenz dose-dependently controlled expression of GLP-1-Fc(mIgG)-Leptin, indicating tunable pharmacologic regulation. The same study states that guanabenz activated a synthetic signal cascade that stimulated secretion of GLP-1 and leptin and that the module supported a therapeutic program in a mouse metabolic syndrome model.
Compared with CAR-NK
chimeric trace-amine-associated receptor 1 and CAR-NK address a similar problem space because they share recombination, signaling.
Shared frame: same top-level item type; shared target processes: recombination, signaling
Relative tradeoffs: appears more independently replicated; looks easier to implement in practice.
Compared with synthetic promoters
chimeric trace-amine-associated receptor 1 and synthetic promoters address a similar problem space because they share recombination, transcription.
Shared frame: same top-level item type; shared target processes: recombination, transcription
Relative tradeoffs: appears more independently replicated; looks easier to implement in practice.
chimeric trace-amine-associated receptor 1 and synthetic promoters containing CREB1-specific cAMP response elements address a similar problem space because they share recombination, signaling, transcription.
Shared frame: same top-level item type; shared target processes: recombination, signaling, transcription; shared mechanisms: camp/pka-mediated creb1 activation
Ranked Citations
- 1.