Source 1primary paper2012Proceedings of the National Academy of Sciences
Toolkit/pharmaceutically controlled designer circuit
pharmaceutically controlled designer circuit
Also known as: designer signaling cascade, synthetic signal cascade
Taxonomy: Mechanism Branch / Architecture. Workflows sit above the mechanism and technique branches rather than replacing them.
Summary
The pharmaceutically controlled designer circuit is a synthetic multi-component signaling cascade activated by the clinically licensed antihypertensive drug guanabenz. In the reported system, guanabenz drives dose-dependent expression and secretion of a GLP-1-Fc(mIgG)-Leptin output relevant to metabolic syndrome treatment.
Usefulness & Problems
Why this is useful
This tool provides pharmacological control over a synthetic signaling program using guanabenz as the input. It is useful for coupling a clinically licensed small molecule to regulated production and secretion of therapeutic protein outputs.
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
It addresses the problem of externally controlling a designer therapeutic gene circuit with a drug input. Specifically, it enables dose-dependent regulation of GLP-1-Fc(mIgG)-Leptin expression through a synthetic signal cascade.
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
Taxonomy & Function
Primary hierarchy
Mechanism Branch
Architecture: A composed arrangement of multiple parts that instantiates one or more mechanisms.
Techniques
Computational DesignTarget processes
recombinationsignalingtranscriptionInput: Chemical
Implementation Constraints
Implementation requires guanabenz as the chemical inducer and a synthetic circuit encoding the GLP-1-Fc(mIgG)-Leptin output. The available evidence does not provide construct architecture, delivery method, promoter design, or expression system details.
The supplied evidence does not specify the molecular components of the cascade, the host cell type, dynamic range, kinetics, or off-target effects. Independent replication is not documented in the provided material, and validation appears limited to the original report.
Validation
Cell-freeBacteriaMammalianMouseHumanTherapeuticIndep. Replication
Observations
successMousetherapeutic use
Inferred from claim c4 during normalization. In mice developing symptoms of metabolic syndrome, the three-in-one treatment strategy simultaneously attenuated hypertension, hyperglycemia, obesity, and dyslipidemia. Derived from claim c4. Quoted text: 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
Source:
successMousetherapeutic use
Inferred from claim c4 during normalization. In mice developing symptoms of metabolic syndrome, the three-in-one treatment strategy simultaneously attenuated hypertension, hyperglycemia, obesity, and dyslipidemia. Derived from claim c4. Quoted text: 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
Source:
successMousetherapeutic use
Inferred from claim c4 during normalization. In mice developing symptoms of metabolic syndrome, the three-in-one treatment strategy simultaneously attenuated hypertension, hyperglycemia, obesity, and dyslipidemia. Derived from claim c4. Quoted text: 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
Source:
successMousetherapeutic use
Inferred from claim c4 during normalization. In mice developing symptoms of metabolic syndrome, the three-in-one treatment strategy simultaneously attenuated hypertension, hyperglycemia, obesity, and dyslipidemia. Derived from claim c4. Quoted text: 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
Source:
successMousetherapeutic use
Inferred from claim c4 during normalization. In mice developing symptoms of metabolic syndrome, the three-in-one treatment strategy simultaneously attenuated hypertension, hyperglycemia, obesity, and dyslipidemia. Derived from claim c4. Quoted text: 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
Source:
successMousetherapeutic use
Inferred from claim c4 during normalization. In mice developing symptoms of metabolic syndrome, the three-in-one treatment strategy simultaneously attenuated hypertension, hyperglycemia, obesity, and dyslipidemia. Derived from claim c4. Quoted text: 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
Source:
successMousetherapeutic use
Inferred from claim c4 during normalization. In mice developing symptoms of metabolic syndrome, the three-in-one treatment strategy simultaneously attenuated hypertension, hyperglycemia, obesity, and dyslipidemia. Derived from claim c4. Quoted text: 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
Source:
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 source4 linked approval claimsfirst-pass slug pharmaceutically-controlled-designer-circuit
We have designed a unique therapeutic strategy in which the clinically licensed antihypertensive drug guanabenz (Wytensin) activates a synthetic signal cascade
Source:
activation mechanismsupports
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
Source:
dose responsive controlsupports
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
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:
therapeutic effectsupports
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
Source:
Comparisons
Source-backed strengths
The reported system is activated by guanabenz and supports dose-dependent control of transgene expression. It was described as a synthetic signal cascade that stimulates secretion of GLP-1 and leptin, indicating functional coupling between drug input and therapeutic output.
Ranked Citations
- 1.