John Sheridan


Research Mentor:

Dr. Robert Tarran, PhD


Clinical Co-mentor

Dr. Ray Coakley, MD

Home Department Cell & Molecular Physiology
Project Description John is investigating the role of estrogen in observed gender differences in cystic fibrosis (CF) patients. Specifically, CF women exhibit an accelerated decline in lung function and have reduced survival rates compared to CF men. Cystic Fibrosis is a genetic disease that results from a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR). As a result, CF patients are not able to secrete Cl- to maintain proper airway surface liquid (ASL) volumes. The ASL acts as a barrier to trap bacteria and irritants that is then cleared from the lungs. However, there is an alternative Cl- channel, the Ca2+-activated Cl- channel, which can regulate airway hydration. Ca2+ signaling usually has two phases. The first phase is achieved by stimulating P2Y2 receptors with ATP to raise intracellular IP3, which stimulates Ca2+ release from the endoplasmic reticulum. This is thought to trigger stromal interacting molecule 1 (STIM1) to relocate along microtubules towards the plasma membrane where it activates Ca2+ influx through the Ca2+ channel Orai1, which is the second phase of Ca2+ signaling.

The Tarran lab has previously shown that when estrogen levels are high in CF women there is a 50% decrease in Ca2+-activated Cl- secretion, which is likely a consequence of impaired Ca2+ influx due to elevated E2 levels. Interestingly, normal females taking oral contraceptives exhibited significantly reduced Ca2+-activated Cl- secretion throughout their cycle, suggesting that synthetic estrogens may be more efficacious at inhibiting Ca2+ entry than E2. This leads to several questions that John will be investigating: 1) what is the molecular mechanism whereby estrogen receptors inhibit Ca2+ influx, 2) do synthetic sex hormones lead to abnormal Ca2+ homeostasis in vitro and 3) do they decrease Cl- secretion and increase mucus dehydration in vivo? It is expected that data obtained during the course of this research will direct CF caregivers towards prescribing oral contraceptives that do not inhibit CF Cl- secretion, which may help reduce the gender disparity in CF lung disease and help prolong the lives of CF females.