TRPM8 in eye health and disease

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Dry eye disease (DED) is a multifactorial disease of the ocular surface characterized by a loss of tear film homeostasis. DED is one of the most common ophthalmological disorders, affecting 5-50% of populations world- wide, with a higher apparent incidence in females and aging populations. Symptoms associated with DED include ocular pain, irritation, dysesthesia, and blurred vision, which are major causes of visits to optometry and ophthalmology clinics. DED affects quality of life significantly and thus is a major public health concern. Despite the gravity of DED, the current treatments for DED are limited. Recent studies have uncovered the role of ocular sensory neurons, particularly cold thermoreceptor neurons, in the etiology of DED as well as ocular physiology. Furthermore, recent studies highlight the role of the cold and menthol receptor TRPM8 in cold sensory neurons in eye health and disease. The proposed research seeks to address the mechanism of ligand-dependent gating by TRPM8 and to develop agonists targeting TRPM8 to relieve DED, dry eye discomfort, and ocular pain. Toward these goals, we will employ a combination of structural biology, electrophysiology, chemical biology, and animal studies to interrogate the roles of TRPM8 in ocular physiology and pathophysiology as well as its pharmacological interventions. Taken together, successful completion of this work will provide the framework for therapeutic development on TRPM8, which will have far-reaching implications in treating ocular disorders.