TRPM8 in eye health and disease

Project Summary Dry eye disease (DED) is a complex, multifactorial disease of the ocular surface characterized by a loss of tear film homeostasis, with symptoms including ocular discomfort and visual disturbance. DED is one of the major reasons for visits to optometry and ophthalmology clinics in U.S., with a higher apparent incidence and prevalence in females and the elderly. With its negative impact on quality of life, DED is a major public health concern. Despite the gravity of DED, current treatments are limited. This strongly suggests that new targets with novel mechanisms of action are needed. Recent studies have uncovered the role of ocular sensory neurons in ocular physiology and the etiology of DED, especially highlighting the role of the cold and menthol receptor, TRPM8, in ocular pain as well as basal tear flow and hydration of the ocular surface. TRPM8 is a valid target for the treatment of DED, but the complex conformational landscape of TRPM8 has hampered drug development. Our primary objectives are to gain a comprehensive understanding of the mechanism by which TRPM8 is gated by ligands and to design and develop novel TRPM8-modulating compounds using structural biology, chemical biology, medicinal chemistry, in vitro and ex vivo electrophysiology, imaging, and animal model studies. Taken together, successful completion of this work will provide the framework for TRPM8-targeted therapeutic development as well as reveal the molecular basis for ligand gating of TRPM8 – with far-reaching implications in treating ocular disorders.