New therapeutic strategies for asthma are needed to better control disease symptoms and improve quality of life. Recommended first-line drugs (inhaled corticosteroids and -adrenergic agonists) do not always control symptoms, disease may become resistant, and side effects can occur. Recently, it was shown that airway smooth muscle (ASM) express ?-amino butyric acid type A receptors (GABAAR) of the ?4/?5 subtype and corresponding subtype selective agonists cause ASM relaxation. Importantly, cells that participate in inflammation (T-lymphocytes and cells of monocyte/macrophage lineage; IC) have also been shown to express functional GABAAR, including the a4 subtype, and reactivity of these cells can be suppressed by GABAAR modulating agents. Despite the growing appreciation of GABAAR signaling in asthma cell types, a strategy that unifies and targets GABAAR responses has not been developed or exploited therapeutically. The long-term goal of our research is to develop safer and more effective asthma drugs by way of our objective to identify GABAAR subunit selective compounds with activity and specificity for affected lung tissues. Our central hypothesis is that ASM and inflammatory cells (IC) express GABAARs with a limited and overlapping subset of ?-subunits that can be targeted with selective agonists; thus providing desired therapeutic activity (suppression of both ASM hyperresponsiveness and inflammation) while avoiding adverse off-target effects. Targeting GABAAR common to both ASM and IC is a compelling asthma strategy because ASM cells can modulate local immune reactivity and inflammatory mediators can influence ASM responsiveness The rationale is that targeting GABAAR in the lung would have drug design advantages because: i) a single drug substance is expected to affect two cell types (ASM and IC) that conspire in asthma pathophysiology; ii) safety is expected to be improved by avoiding corticosteroid use, and; iii) GABAAR agents are prescribed extensively and have a long history of clinical use. We will pursue our central hypothesis by way of three Specific Aims: 1) identify GABAAR subtypes by library screening that have common activity in ASM and IC; 2) establish efficacy of GABAAR ligands in asthma disease models; and, 3) develop selective GABAAR ligands with optimal pharmacological properties.
These Aims will yield significant expected outcomes. First, library screening will reveal a detailed relationship between ?-subunit GABAAR selectivity and pharmacological efficacy in the lung. Second, compounds optimized for ?-subunit selectivity will be efficacious in animal asthma models demonstrating pharmacological proof-of-concept. Third, lead compounds will have pharmaceutical properties suitable for safe oral dosage. The positive impacts of these outcomes are an innovative therapeutic strategy for asthma that unifies GABAAR signaling in the lung, expanded knowledge of (and tools to study) lung signaling mechanisms, and ultimately improved patient care from a new drug choice with a fundamentally novel mode of action, improved dosage form, and reduced potential for adverse effects compared to current drugs.
The proposed research is relevant to public health because asthma continues to have a significant healthcare impact; with about 8.2% of the population afflicted in the U.S. alone resulting in annual health care costs of over $56 billion. The growing burden of asthma, especially in pediatric and minority populations, demands novel therapies to better manage symptoms, reduce side effects, and improve drug delivery. The research is relevant to NIH's mission because fundamental knowledge created by systematically probing GABAAR signaling in the lung will give the research community invaluable tools to better understand the pathophysiology and possible treatments of other diseases influenced by GABAAR activity.
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