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.
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