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)
Figure 1 Gα12 signaling and RhoA-dependent activation of the PI3K/ROCK axis
![](data:image/png;base64,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)
Figure 2 Gα12 siRNA attenuates carbachol-induced MLC (myosin light chain) phosphorylation in vivo. Reduced MLC phosphorylation indicates human airway smooth muscle relaxation. Carbachol activates Gα12 -coupled M3 muscarinic receptors in human airway smooth muscle.
Invention Summary:
Airway Hyperresponsiveness (AHR), a hallmark of asthma, represents exaggerated airway narrowing in response to contractile agonists such as acetylcholine. Human airway smooth muscle cells (HASMCs) mediate AHR by shortening in response to contractile agonists. Inhibition of calcium sensitization pathways in human airway smooth muscle has been shown to be an effective method of inducing bronchodilation. Due to off target effects in vascular smooth muscle, however, clinical trials of bronchodilators targeting calcium sensitization pathways have been precluded. Accordingly, there is a strong need for alternative approaches to the clinical management of airway obstruction in asthma, chronic obstructive pulmonary disease (COPD), and other inflammatory lung diseases. About 50% of asthma patients currently have uncontrolled symptom. This research approach may overcome the limitations of existing therapy.
Rutgers scientists identified a novel target - Gα12 signaling - for relaxing human airway smooth muscle. This discovery demonstrates that Gα12 plays a crucial role in human airway smooth muscle contraction via RhoA-dependent activation of the PI3K/ROCK axis (Figure 1). In human asthma models, inhibition of Gα12 signaling serves as an effective and novel method of inducing bronchodilation, a clinically desirable outcome in asthma treatment (Figure 2).
Targeting Gα12 signaling may elucidate novel therapeutic targets in asthma. In addition, inhibition of RhoA activation induces bronchodilation in human precision-cut lung slices. Taken together, these findings provide alternative approaches to the clinical management of airway obstruction in asthma, COPD, and any other inflammatory lung disease.
Market Applications:
- Agents and method for therapeutic treatment of asthma, chronic obstructive pulmonary disease, cystic fibrosis and other inflammatory lung diseases.
- A method for identifying an agent which inhibits contraction or promotes relaxation of an airway smooth muscle cell.
Advantages:
- Novel bronchodilators
- New modality of treatment
- Tissue-specific target
Intellectual Property & Development Status:
Patent pending. Available for licensing and/or collaboration.