Human Ocular Surface Electrophysiology
人眼表面电生理学
基本信息
- 批准号:10591279
- 负责人:
- 金额:$ 21.93万
- 依托单位:
- 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:
- 关键词:AdultAffectAnimalsApicalAwardCalciumCaringCarrier ProteinsCauterizeCell Culture TechniquesCell LineChloride ChannelsClinical ResearchClinical TrialsCorneaCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDataDry Eye SyndromesDuct (organ) structureEducational workshopElectrophysiology (science)Epithelial CellsEpitheliumExperimental Animal ModelExperimental ModelsEyeEye diseasesFDA approvedFilmFluids and SecretionsGoalsHomeostasisHumanImpairmentInflammatoryIon TransportIonsKnowledgeLearningLiquid substanceMeasurementMeasuresMembraneMentorsMethodsModelingMusOphthalmologistOphthalmologyOsmolar ConcentrationPathway interactionsPatientsPharmaceutical PreparationsPharmacodynamicsPhase II Clinical TrialsPhenolsulfonphthaleinPotassium ChannelPrevalenceResearchResearch PersonnelResidenciesRewardsRoleScientific Advances and AccomplishmentsSignal TransductionSocietiesStratified EpitheliumSurrogate MarkersSymptomsTestingTherapeuticTrainingTranslatingTranslational ResearchTriazinesWorkabsorptionanimal model developmentburden of illnesscareer developmentcell injuryconjunctivacorneal epitheliumcostdrug candidatedrug developmentdrug discoverydrug efficacyelectrical potentialepithelial Na+ channelexperienceeye drynesshigh throughput screeninghuman datahuman subjectin vivoin vivo evaluationinhibitorlacrimalmathematical modelmouse modelnovelnovel diagnosticsnovel therapeutic interventionocular surfaceocular surface diseasepharmacologicprogramsskillssmall moleculetargeted treatmenttool 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
这是一个为期5年的指导K08奖,以促进尼尔Pasricha博士,眼科医生与
角膜专科培训,眼表眼睛翻译研究的独立研究者。一
在UCSF,科学顾问和教学工作的经验丰富的导师强大的团队将协助博士Pasricha的
研究技能转移,包括眼表电生理学,人类角膜上皮细胞
培养模型,用于小分子药物发现的高通量筛选,实验小鼠模型,
和人类受试者临床研究。
该研究的重点是干眼病(DED),这是眼科的一个主要未满足的需求,其特征是
泪膜稳态受损,伴有眼部症状。目前只有四种FDA批准的
DED的治疗,每一种都只靶向炎症通路,疗效有限。眼
角膜和结膜表面由表达离子转运的分层上皮细胞构成
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。目标
这项研究的目的是发现和推进促进泪液分泌的候选药物
是由眼表的上皮细胞造成的
本研究采用了一种新的眼表电位差(OSPD)的方法在动物研究中介绍
并在加州大学旧金山分校实习期间将其应用于人类。OSPD测量电势
在上皮细胞中产生的来自顶膜和基膜离子转运蛋白的差异。在目标1中,体内
小鼠中的OSPD测量将研究离子转运蛋白在眼表液体转运中的作用,
特别关注氯和钾通道。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,
靶向钙激活氯离子通道以增加泪液分泌的候选药物
DED。目标3将使用健康成人体内人体OSPD测量来测试促分泌药物
2期临床试验的候选人,激活CFTR氯离子通道。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,推进
基本了解眼表面离子转运,并将这些知识转化为新的
包括DED在内的眼表疾病的诊断和治疗策略。
项目成果
期刊论文数量(0)
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Neel Dave Pasricha的其他文献
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