TRPM8 in eye health and disease

TRPM8 在眼睛健康和疾病中的作用

基本信息

批准号：
10405018
负责人：
Jiyong Hong
金额：
$ 39.77万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405018
关键词：
Address Affect Afferent Neurons Age Aging Agonist Animal Model Animals Binding Sites Biology Blinking Blurred vision Calcium Chemical Structure Chemicals Clinic Complex Cryoelectron Microscopy Data Development Disease Dry Eye Syndromes Dryness Dysesthesias Economic Burden Electrophysiology (science)Esthesia Etiology Exhibits Eye Female Film Force of Gravity Functional disorder Goals Health Homeostasis Human Hydration status Image In Vitro Incidence Intervention Ion Channel Laboratories Lead Ligand Binding Ligands Lipids Liquid substance Menthol Molecular Molecular Conformation Mus Mutagenesis Neurons Ocular Physiology Ophthalmologic Surgical Procedures Ophthalmology Optometry Osmolalities Pain Patients Permeability Pharmaceutical Chemistry Pharmacology Play Population Public Health Quality of life Regulation Reporting Research Rest Role Signal Transduction Site-Directed Mutagenesis Societies Structure Study models Symptoms Therapeutic Therapeutic Intervention Thermoreceptors Trigeminal System Visit Work analog antagonist associated symptom base clinically relevant combat design eye dryness field study flexibility icilin insight interest irritation member mouse model novel novel therapeutics ocular pain ocular surface receptor side effect structural biology surgical pain therapeutic development

项目摘要

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.

干眼病（DED）是一种眼表多因素疾病，其特征是泪膜丧失体内平衡。 DED 是最常见的眼科疾病之一，影响着世界上 5-50% 的人口广泛，女性和老年人群的发病率明显较高。与 DED 相关的症状包括眼痛、刺激、感觉迟钝和视力模糊，这些是去验光和视力检查的主要原因眼科诊所。 DED 严重影响生活质量，因此是一个主要的公共卫生问题。尽管由于 DED 的严重性，目前 DED 的治疗方法有限。最近的研究揭示了眼部的作用感觉神经元，特别是冷热感受神经元，在 DED 的病因学以及眼生理学中。此外，最近的研究强调了冷和薄荷醇受体 TRPM8 在冷感觉神经元中的作用在眼睛健康和疾病方面。拟议的研究旨在解决配体依赖性门控的机制 TRPM8 并开发针对 TRPM8 的激动剂，以缓解干眼症、干眼不适和眼痛。走向为了实现这些目标，我们将结合结构生物学、电生理学、化学生物学和动物学研究探讨 TRPM8 在眼生理学和病理生理学中的作用及其药物干预。总而言之，这项工作的成功完成将为 TRPM8的治疗开发，这将对治疗眼部疾病产生深远的影响。