The long-term goal of this proposal is to understand the mechanism of action of calcium signaling pathways in airway smooth muscle in order to identify novel bronchodilators for the clinic. The immediate goals for this proposal are twofold. The research will provide an understanding (at the cellular level) of how a novel bronchodilator, UCL 1684, modulates SK channels and causes airway smooth muscle relaxation. The research will determine the mechanism by which SR SK potassium channels affect sarcoplasmic reticulum and cytosolic calcium load, excitability and contractility of ASM cells using calcium imaging and electrophysiology of airway smooth muscle cells. Second, the research will investigate UCL 1684 efficacy as a bronchodilator in vivo in animal models of asthma and models of ?2 agonist tachyphylaxis. The approach will be to use whole animal plethysmography, and the forced oscillation techniques on asthmatic mice to evaluate UCL 1684 effects on airway severity and airway resistance, respectively. In addition, the experiments will examine UCL1684 effects on remodeling during asthma with a particular emphasis on its effects on airway muscle remodeling.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI113724-01
Application #
8770358
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Minnicozzi, Michael
Project Start
2014-07-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Health Science Center
Department
Physiology
Type
Schools of Medicine
DUNS #
City
San Antonio
State
TX
Country
United States
Zip Code
78229
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Brenner, Robert (2014) Knockout of the BK β2 subunit reveals the importance of accessorizing your channel. J Gen Physiol 144:351-6