Date of Award
Doctor of Philosophy (PhD)
Pharmacology and Experimental Therapeutics
Asthma is a disease characterized by nonspecific and exaggerated airway narrowing, termed airway hyperresponsiveness (AHR), which involves the excessive contraction of airway smooth muscle. Despite the fact that airway smooth muscle is widely studied and understood to play a role in AHR, little is known about the specifics of that role. Our laboratory recently found that Kv7 potassium (K+) channels are expressed in airway smooth muscle cells (ASMCs). Kv7 channels are voltage sensitive K+ channels whose outward flux of K+ ions promotes a negative resting membrane voltage in excitable cells, thereby opposing electrical excitability. Inhibition of K+ channels is known to induce membrane depolarization, resulting in the activation of voltage-sensitive calcium (Ca2+) channels (VSCCs) and an increase in intracellular Ca2+ concentrations. Our laboratory hypothesizes that Kv7 channels are also involved in the regulation of ASMC excitability and therefore in the regulation of airway diameter. Pharmacological Kv7 channel activators attenuated bronchoconstrictor-induced airway constriction, leading us to speculate that Kv7 channels may be novel therapeutic targets for the treatment of asthma. In order to understand the role and regulation of Kv7 channels in airway smooth muscle and test my hypothesis that Kv7 channels represent a novel therapeutic target for asthma, I propose the following aims: Aim 1: Elucidate the mechanism by which bronchoconstrictor agonists regulate Kv7 channels in airway smooth muscle. Aim 2: Determine the efficacy of Kv7 channel activators in attenuating agonist-induced bronchoconstriction and explore their therapeutic potential for the treatment of asthma. By accomplishing these aims, the intention is to understand the role that Kv7 channels play in ASMCs and the regulation of airway diameter and determine if Kv7 channel activators represent a novel class of asthma therapeutics.
Haick, Jennifer, "Examining the Regulation of Kv7 K+ Channels in Airway Smooth Muscle Cells and Their Potential as Novel Therapeutic Targets for the Treatment of Asthma" (2017). Dissertations. 2588.
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Copyright © 2017 Jennifer Haick
Available for download on Monday, December 21, 2020