TRPM8 in eye health and disease

干眼病(DED)是一种以泪膜丢失为特征的眼表多因素疾病。 动态平衡。DED是最常见的眼科疾病之一，影响着全球5%-50%的人口。 范围广，在女性和老龄化人口中明显发病率较高。与DED相关的症状 包括眼睛疼痛、刺激、感觉障碍和视力模糊，这些都是导致验光和治疗的主要原因 眼科诊所。DED对生活质量有很大影响，因此是一个主要的公共卫生问题。尽管 DED的严重性，目前对DED的治疗是有限的。最近的研究揭示了眼球运动的作用 感觉神经元，特别是冷热感受器神经元在DED的病因和眼生理中的作用。 此外，最近的研究强调了寒冷和薄荷醇受体TRPM8在寒冷感觉神经元中的作用 在眼睛健康和疾病方面。拟议的研究试图解决配体依赖门控的机制 开发针对TRPM8的激动剂，以缓解DED、干眼不适和眼痛。冲向 为了实现这些目标，我们将结合结构生物学、电生理学、化学生物学和动物 TRPM8在眼生理和病理生理学中的作用及其研究进展 药物干预。综上所述，这项工作的成功完成将为 TRPM8的治疗进展，将对眼科疾病的治疗具有深远的意义。

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.