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.

项目摘要这是一项为期5年的K08奖，以促进Neel Pasricha博士的过渡，角膜子专科训练，向眼部表面眼翻译研究中的独立研究者。一个 UCSF，科学顾问和教学工作的强大经验丰富的导师将有助于Pasricha博士研究技能转移，包括眼表电生理学的培训，人角膜上皮细胞培养模型，小分子药物发现的高通量筛查，实验小鼠模型，和人类学科临床研究。该研究的重点是干眼症（DED），这是眼科的主要未满足的需求，其特征是通过眼部症状造成的撕裂膜体内平衡受损。目前只有四个FDA批准 DED的疗法，每个疗法仅针对炎症途径，并且效率有限。眼睛由角膜和结膜组成的表面由表达离子转运的分层上皮细胞衬里促进活跃的液体分泌或滥用的蛋白质调节泪液体积和渗透压。目标拟议的研究是发现并推进候选药物以促进泪液分泌通过衬在眼表面的上皮细胞。这项研究利用了动物研究中引入的新型眼表势差（OSPD）方法并在我在UCSF的长期存在期间用于人类使用。 OSPD测量电势顶端和碱性膜离子转运蛋白的上皮产生的差异。在AIM 1中，体内小鼠中的OSPD测量将研究离子转运蛋白在肌表面流体转运中的作用，并以特别关注氯化物和钾通道。 AIM 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化物通道的药物候选者增加泪液分泌以治疗 ded。 AIM 3将在健康成年人中使用体内人类OSPD测量测量来测试促分泌药物在第2阶段临床试验中候选者激活CFTR氯化物通道。长期职业发展目标是建立一个强大的跨学科研究计划对眼表离子传输的基本了解，并将其转化为新颖眼表疾病的诊断和治疗策略，包括DED。