Asthma is a chronic inflammatory disease of the airways present in 8% of the US population. It is associated with billions of dollars in health car costs and poorly controlled asthma is the leading medical cause of school absenteeism. Although research has made great strides in elucidating the underlying mechanisms involved in asthma, there have been no new classes of therapeutics for many decades resulting in up to 40% of asthmatics having incompletely controlled symptoms. Components of the most widely used asthma medications, long acting inhaled beta agonists, are associated with an increased death rate from asthma and are currently under FDA-mandated review for long term safety. Our laboratory discovered the expression of GABAA receptors on airway smooth muscle and demonstrated that activation of these classic neuronal receptors could relax airway smooth muscle. We then demonstrated that a complete GABAergic system existed in multiple lung cells including ionotropic GABAA receptors, metabotropic GABAB receptors, the enzymes that synthesize GABA (glutamic acid decarboxylase) and GABA transporters. The GABAA receptors that relax airway smooth muscle contain either an ?4 or ?5 subunit. Remarkably we have now discovered that key inflammatory cells that mediate allergic lung inflammation also express ?4 subunit-containing GABAA channels. In the current proposal we continue our collaboration with a leading GABAA ligand medicinal chemist to identify novel ligands that activate ?4 or ?5 subunit-containing GABAA channels that will both relax airway smooth muscle and inhibit lung inflammation-the two key pathologic components of asthma. We seek to synthesize derivatives of novel ligands that will be delivered to a murine asthma model by inhalation that would not penetrate the CNS to avoid undesired effects.
In aim 1 we will deliver aerosols of GABAA ?4 or ?5 ligands to asthmatic mice while challenging their airways with a contractile mediator and measure resulting tissue concentrations in plasma, lung, liver and brain.
In aim 2 we will test the ability of these GABAA ligands to relax isolated human airway smooth muscle strips and determine the link between their control of membrane potential and intracellular signaling events that control contraction.
In aim 3 we will utilize mice lacking GABAA ?4 subunits to demonstrate the critical role of GABAA ?4 receptors in allergic lung inflammation. We will demonstrate the role of GABAA ?4 receptors in regulating membrane potential and lymphocyte activation and proliferation. These approaches offer a radical new therapy, a translational therapeutic approach and a novel paradigm for targeting two key components of asthma; inflammation and airway smooth muscle hyperresponsiveness.
The central goal of this proposal is to identify novel ligands for GABAA receptors expressing ?4 or ?5 subunits that can be delivered by aerosol to the lungs for asthma therapy. These ligands will target both airway smooth muscle and lung inflammatory cells and undergo rapid systemic clearance without CNS penetration.
|Mikami, Maya; Perez-Zoghbi, Jose F; Zhang, Yi et al. (2018) Attenuation of Murine and Human Airway Contraction by a Peptide Fragment of the Cytoskeleton Regulatory Protein Gelsolin. Am J Physiol Lung Cell Mol Physiol :|
|Forkuo, Gloria S; Nieman, Amanda N; Kodali, Revathi et al. (2018) A Novel Orally Available Asthma Drug Candidate That Reduces Smooth Muscle Constriction and Inflammation by Targeting GABAA Receptors in the Lung. Mol Pharm 15:1766-1777|
|Matoba, Atsuko; Matsuyama, Nao; Shibata, Sumire et al. (2018) The free fatty acid receptor 1 promotes airway smooth muscle cell proliferation through MEK/ERK and PI3K/Akt signaling pathways. Am J Physiol Lung Cell Mol Physiol 314:L333-L348|
|Matsuyama, Nao; Shibata, Sumire; Matoba, Atsuko et al. (2018) The dopamine D1 receptor is expressed and induces CREB phosphorylation and MUC5AC expression in human airway epithelium. Respir Res 19:53|
|Mikami, Maya; Zhang, Yi; Kim, Benjamin et al. (2017) Dexmedetomidine's inhibitory effects on acetylcholine release from cholinergic nerves in guinea pig trachea: a mechanism that accounts for its clinical benefit during airway irritation. BMC Anesthesiol 17:52|
|Yocum, Gene T; Turner, Damian L; Danielsson, Jennifer et al. (2017) GABAA receptor ?4-subunit knockout enhances lung inflammation and airway reactivity in a murine asthma model. Am J Physiol Lung Cell Mol Physiol 313:L406-L415|
|Forkuo, Gloria S; Nieman, Amanda N; Yuan, Nina Y et al. (2017) Alleviation of Multiple Asthmatic Pathologic Features with Orally Available and Subtype Selective GABAA Receptor Modulators. Mol Pharm 14:2088-2098|
|Jahan, Rajwana; Stephen, Michael Rajesh; Forkuo, Gloria S et al. (2017) Optimization of substituted imidazobenzodiazepines as novel asthma treatments. Eur J Med Chem 126:550-560|
|Ling, Yuye; Yao, Xinwen; Gamm, Ute A et al. (2017) Ex vivo visualization of human ciliated epithelium and quantitative analysis of induced flow dynamics by using optical coherence tomography. Lasers Surg Med 49:270-279|
|Mikami, Maya; Zhang, Yi; Danielsson, Jennifer et al. (2017) Impaired Relaxation of Airway Smooth Muscle in Mice Lacking the Actin-Binding Protein Gelsolin. Am J Respir Cell Mol Biol 56:628-636|
Showing the most recent 10 out of 49 publications