Roles of CaSR in ocular surface health and disease

ABSTRACT Dry eye disease (DED) is a major health problem. Reduced ocular surface hydration is a key pathology in DED, which causes symptoms and can lead to ocular surface inflammation and damage. Current FDA- approved treatments for DED include artificial tears and anti-inflammatory agents that have variable and limited efficacy. Here we propose a novel target for treatment of DED. The target is the extracellular Ca2+-sensing receptor (CaSR) that has well-known modulatory effects on epithelial ion transport in various tissues such as intestine and kidney. We found prominent CaSR expression in mouse and human corneal and conjunctival epithelial cells. CaSR activation in the ocular surface reduced CFTR-mediated Cl- secretion, confirming key roles of CaSR ocular surface ion transport. Importantly, we found that CaSR inhibition by NPS-2143 stimulates CFTR-mediated Cl- secretion in the ocular surface and increases tear fluid volume in mice by ~100%. Here we will perform key translational studies for CaSR inhibitors, by testing them in clinically relevant animal and human cell models of DED to advance them towards clinical testing (Aim 1). We will also study the roles and mechanisms of CaSR effect in ocular surface ion transport and health (Aim 2). The proposed studies can potentially lead to clinical testing of CaSR inhibitors for DED in the very near future. By identifying a novel treatment, these studies can ultimately reduce DED morbidity. Lastly, by identifying roles and mechanisms of CaSR in ocular surface, this project can also identify novel disease mechanisms for DED.