Ion channels & Ionocyte Physiology
There are at least 300 unique genes in the human genome encoding the pore-forming subunits of ion channels. The classification of ion channels typically reflects their functional properties, such as the ions which they pass (e.g., Na+, K+, Ca2+,and Cl–) or the respective gating mechanisms (e.g., by ligands, membrane voltage, or second messengers). The opening and closing of ion channels carry out many critical cellular and physiological processes including cell volume regulation, maintenance of cellular and transepithelial membrane potentials, transport of osmolytes and the osmotic movement of water, and the initiation and propagation of action potential firing. Ion channel dysfunction is thus the pathogenesis for a multitude of human channelopathies, including disorders of the brain/central nervous system (e.g., epilepsy), heart (e.g., arrhythmia), lung (e.g., cystic fibrosis), intestine (e.g., constipation and diarrhea), kidney (e.g., stone formation), muscle (e.g., muscular dystrophy), and sinuses and inner ear (e.g., migraines,deafness, and tinnitus).
At National Jewish Health, my research focus is on understanding the function and regulation of ion channels and ion-secreting cells (“ionocytes”) on the airway surface, and applying this knowledge to the understanding and treatment of disease. I work specifically with the Cl– channel, the cystic fibrosis transmembrane conductance regulator (CFTR), which is the primary route of Cl– secretion in the airway and critical to maintaining healthy airway surface moisture. Genetic mutations of CFTR result in cystic fibrosis disease (CF). I perform basic and translational research aimed at understanding CFTR function, cellular pathways that regulate CFTR expression and activity, and developing novel therapies for enhancing CFTR function to treat CF.
Ongoing Projects and Upcoming Manuscripts
Electrophysiological characterization of ion channel function in primary nasal epithelia. We perform electrophysiological studies on primary airway epithelial cell cultures from donors with and without CF. We aim to characterize the influence of electrical and chemical forces on ion transport processes and measurements of CFTR function.
Bratcher PE, Yadav S, Shaughnessy CA, Thornell IM, and Zeitlin PL. Effect of apical chloride concentration on measurement of responses to CFTR modulation in airway epithelia cultured from nasal brushings. [in review at Physiol Rep]
Shaughnessy CA, Yadav S, Thornell IM, Zeitlin PL, and Bratcher PE. Influence of electrical and chemical gradients on CFTR activity measurements in human airway epithelia.
Yadav S, Shaughnessy CA, Zeitlin PL, and Bratcher PE. Down-regulation of the epithelial sodium channel (ENaC) in human airway epithelia in response to low temperature incubation.
Pre-clinical studies on pharmacological therapies to enhance CFTR function in the airway. I am interested in characterizing the endogenous cellular pathways that regulate activity of CFTR in the airway. These cellular pathways could be pharmacologically targeted to increase activity of rescued CFTR in patients with cystic fibrosis. To this end, I carry out pre-clinical studies in vitro examining the efficacy and mechanism-of-action of synthetic prostones as novel chloride channel modulators for use in the treatment of cystic fibrosis.
Shaughnessy CA, Yadav S, Zeitlin PL, and Bratcher PE. Lubiprostone as a novel, receptor-mediated activator of CFTR in the airway: in vitro evidence for treatment of F508del and other CFTR mutations. [abstract accepted to the North American Cystic Fibrosis Conference]