Human Ocular Surface Electrophysiology

人眼表面电生理学

基本信息

批准号：
10591279
负责人：
Neel Dave Pasricha
金额：
$ 21.93万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10591279
关键词：
Adult Affect Animals Apical Award Calcium Caring Carrier Proteins Cauterize Cell Culture Techniques Cell Line Chloride Channels Clinical Research Clinical Trials Cornea Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Dry Eye Syndromes Duct (organ) structure Educational workshop Electrophysiology (science)Epithelial Cells Epithelium Experimental Animal Model Experimental Models Eye Eye diseases FDA approved Film Fluids and Secretions Goals Homeostasis Human Impairment Inflammatory Ion Transport Ions Knowledge Learning Liquid substance Measurement Measures Membrane Mentors Methods Modeling Mus Ophthalmologist Ophthalmology Osmolar Concentration Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phase II Clinical Trials Phenolsulfonphthalein Potassium Channel Prevalence Research Research Personnel Residencies Rewards Role Scientific Advances and Accomplishments Signal Transduction Societies Stratified Epithelium Surrogate Markers Symptoms Testing Therapeutic Training Translating Translational Research Triazines Work absorption animal model development burden of illness career development cell injury conjunctiva corneal epithelium cost drug candidate drug development drug discovery drug efficacy electrical potential epithelial Na+ channel experience eye dryness high throughput screening human data human subject in vivo in vivo evaluation inhibitor lacrimal mathematical model mouse model novel novel diagnostics novel therapeutic intervention ocular surface ocular surface disease pharmacologic programs skills small molecule targeted treatment tool development

项目摘要

PROJECT SUMMARY This is a 5-year mentored K08 award to facilitate the transition of Dr. Neel Pasricha, an ophthalmologist with cornea subspecialty training, to an independent investigator in ocular surface eye translational research. A strong group of experienced mentors at UCSF, scientific advisors, and didactic work will assist Dr. Pasricha’s research skills transfer, including training in ocular surface electrophysiology, human corneal epithelial cell culture models, high-throughput screening for small-molecule drug discovery, experimental mouse models, and human subject clinical studies. The research is focused on dry eye disease (DED), a major unmet need in ophthalmology characterized by impaired tear film homeostasis accompanied by ocular symptoms. There are currently just four FDA-approved therapies for DED, each targeting only the inflammatory pathway and having limited efficacy. The ocular surface, comprised of the cornea and conjunctiva, is lined by stratified epithelial cells expressing ion transport proteins that facilitate active fluid secretion or absorption to regulate tear fluid volume and osmolarity. The goal of the proposed research is to discover and advance drug candidates to promote tear fluid secretion by epithelial cells lining the ocular surface. This research utilizes a novel ocular surface potential difference (OSPD) method introduced in animal studies and advanced for use in humans during my residency at UCSF. OSPD measures the electrical potential difference generated across epithelia from apical and basal membrane ion transporters. In Aim 1, in vivo OSPD measurements in mice will investigate the role of ion transporters in ocular surface fluid transport, with particular focus on chloride and potassium channels. Aim 2 will use ex vivo high-throughput screening in primary human corneal epithelial cell cultures and in vivo experimental mouse studies to advance potential drug candidates that target calcium-activated chloride channels to increase tear fluid secretion for treatment of DED. Aim 3 will use in vivo human OSPD measurements in healthy adults to test a pro-secretory drug candidate in phase 2 clinical trial that activates the CFTR chloride channel. The long-term career development goal is to build a robust cross-disciplinary research program that advances the fundamental understanding of ocular surface ion transport and translates that knowledge into novel diagnostic and therapeutic strategies for ocular surface diseases, including DED.

项目概要这是一个为期 5 年的 K08 指导奖，旨在促进 Neel Pasricha 博士的过渡，他是一名眼科医生，角膜亚专业培训，眼表眼睛转化研究的独立研究者。加州大学旧金山分校经验丰富的导师、科学顾问和教学工作组成的强大团队将协助 Pasricha 博士的研究研究技能转移，包括眼表电生理学、人角膜上皮细胞的培训培养模型、小分子药物发现的高通量筛选、实验小鼠模型、和人体临床研究。该研究的重点是干眼病（DED），这是眼科领域一个未满足的主要需求，其特点是泪膜稳态受损并伴有眼部症状目前只有四种药物获得 FDA 批准。针对 DED 的多种疗法，每种疗法均仅针对炎症途径，且疗效有限。表面由角膜和结膜组成，排列着表达离子转运的分层上皮细胞促进主动液体分泌或吸收以调节泪液体积和渗透压的蛋白质。拟议研究的目的是发现和开发促进泪液分泌的候选药物由眼表面的上皮细胞组成。本研究采用了动物研究中引入的新型眼表电位差（OSPD）方法在我在 UCSF 住院期间，OSPD 测量了电位，并在人类中得到了发展。在目标 1 中，体内顶膜和基底膜离子转运蛋白在上皮细胞上产生的差异。小鼠 OSPD 测量将研究离子转运蛋白在眼表液体转运中的作用，其中特别关注氯离子和钾离子通道，目标 2 将使用离体高通量筛选。原代人角膜上皮细胞培养和体内实验小鼠研究以提高潜力靶向钙激活氯离子通道以增加泪液分泌以治疗以下疾病的候选药物 DED。目标 3 将使用健康成人体内的人体 OSPD 测量来测试促分泌药物。激活 CFTR 氯通道的 2 期临床试验的候选人长期职业生涯。发展目标是建立一个强大的跨学科研究计划，推动对眼表面离子传输的基本理解并将该知识转化为新颖的眼表疾病（包括 DED）的诊断和治疗策略。