Asthma is a chronic inflammatory disease of the airways whose global prevalence has taken on pandemic proportions. Although research has made great strides in elucidating the underlying mechanisms involved in asthma, in recent decades relatively few new additions have been made to the pharmacological armamentarium for this disease. Our laboratory has made several novel discoveries: (1) that 3-aminobutyric acid subtype A (GABAA) GABAA channels are expressed on airway smooth muscle cells, (2) that an endogenous GABAergic ligand-receptor system exists in the airway (3) that activation of endogenous airway smooth muscle GABAA channels potentiates relaxation, (4) that GABA (endogenously present in the airway) functions to modulate airway smooth muscle tone, (5) that systemic administration of a GABAA channel agonist administered in vivo attenuates agonist-induced airway constriction and that (6) part of propofol's broncho-relaxant effect is mediated by GABAA channels on airway smooth muscle. Since pharmacologic specificity of ligands/agonists directed at the GABAA channel is dictated by GABAA subunit composition, selective targeting of certain subunits restricted to a given tissue hold promise for improved therapy. Therefore, the goal of this research proposal is to elucidate the importance of airway smooth muscle GABAA channel subunit composition on the modulation of airway smooth muscle tone. The proposed experiments hold promise for determining how airway smooth muscle GABAA channel subunit heterogeneity can be harnessed to optimize relaxation of airway smooth muscle without promoting excessive sedation by globally activating all GABAA channels. The central significance of this proposal is the identification of a novel therapeutic mechanism to relax constricted airway smooth muscle following irritant induced bronchoconstriction. However, this work has the therapeutic potential to broadly impact the control of airway smooth muscle tone in the management of asthma and COPD. The specific therapeutic targeting of GABAA subunits expressed on airway smooth muscle coupled with traditional aerosol delivery methods to the airway, holds promise for a fundamental improvement in the pharmacologic therapy of asthma, a disease lacking in substantial improvements in drug therapy for several decades. This award will allow me to obtain the necessary investigational skills, experimental knowledge base, and fertile collaborative relationships to develop into a successful and independent clinician scientist.

Public Health Relevance

The central significance of this proposal is the identification of a novel therapeutic mechanism to relax constricted airway smooth muscle. This work will harness the underutilized ability of anesthetics to allosterically enhance endogenous airway GABA effects at the airway smooth muscle GABAA channel. This proposal builds upon previous work from our laboratory identifying a limited repertoire of GABAA subunits comprising functional GABAA channels expressed on airway smooth muscle cells. The pharmacologic specific targeting of GABAA subunits expressed on airway smooth muscle coupled with traditional aerosol delivery methods to the airway, holds promise for a fundamental improvement in pharmacologic therapy of asthma, a disease lacking in substantial improvements in drug therapy for several decades. Narrative The central significance of this proposal is the identification of a novel therapeutic mechanism to relax constricted airway smooth muscle. This work will harness the underutilized ability of anesthetics to allosterically enhance endogenous airway GABA effects at the airway smooth muscle GABAA channel. This proposal builds upon previous work from our laboratory identifying a limited repertoire of GABAA subunits comprising functional GABAA channels expressed on airway smooth muscle cells. The pharmacologic specific targeting of GABAA subunits expressed on airway smooth muscle coupled with traditional aerosol delivery methods to the airway, holds promise for a fundamental improvement in pharmacologic therapy of asthma, a disease lacking in substantial improvements in drug therapy for several decades.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08GM093137-05
Application #
8716771
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Cole, Alison E
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$125,685
Indirect Cost
$9,310
Name
Columbia University (N.Y.)
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Bernstein, Kyra; Vink, Joy Y; Fu, Xiao Wen et al. (2014) Calcium-activated chloride channels anoctamin 1 and 2 promote murine uterine smooth muscle contractility. Am J Obstet Gynecol 211:688.e1-10
Gallos, George; Remy, Kenneth E; Danielsson, Jennifer et al. (2013) Functional expression of the TMEM16 family of calcium-activated chloride channels in airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 305:L625-34
Gallos, George; Emala, Charles W (2013) Anesthetic effects on ýý-aminobutyric acid A receptors: not just on your nerves. Anesthesiology 118:1013-5
Gallos, George; Townsend, Elizabeth; Yim, Peter et al. (2013) Airway epithelium is a predominant source of endogenous airway GABA and contributes to relaxation of airway smooth muscle tone. Am J Physiol Lung Cell Mol Physiol 304:L191-7
Gallos, George; Yim, Peter; Chang, Sucie et al. (2012) Targeting the restricted ?-subunit repertoire of airway smooth muscle GABAA receptors augments airway smooth muscle relaxation. Am J Physiol Lung Cell Mol Physiol 302:L248-56