Claudin-18 and pathologic alveolar epithelial permeability
Claudin-18 和病理性肺泡上皮通透性
基本信息
- 批准号:8424854
- 负责人:
- 金额:$ 13.23万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-02-01 至 2018-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAcute Lung InjuryAffectAirAlbuminsAlveolarAnesthesia proceduresApicalAwardBasic ScienceBiologyBloodCaliforniaCessation of lifeChronicClinicalClinical SciencesComplexCoupledCritical CareDataDiseaseEpithelialEpithelial CellsFamilyFibrosisFluid BalanceFunctional disorderFundingGeneticGoalsHealthHumanIn VitroIndividualInflammationInjuryIntegral Membrane ProteinIntegrinsIntestinesIonsK-Series Research Career ProgramsKnockout MiceLaboratoriesLeadLinkLungMediatingMedicineMentorsMentorshipModelingMusMutationNatureOrganPathogenesisPathologicPatientsPatternPermeabilityPhysiciansPreparationProteinsPulmonary PathologyRNA SplicingRegulationResearchResearch PersonnelResearch ProposalsRespiratory FailureRodentRoleSan FranciscoScientistStructureSupportive careTestingTight JunctionsTissuesTrainingTransforming Growth FactorsUnited StatesUniversitiesVariantWorkalveolar epitheliumbasecareercareer developmentclaudin 3claudin-1 proteinclinically relevantimprovedin vivoinstructorlung injurymacromoleculemortalitymultidisciplinarynovelnovel therapeuticspostnatalprofessorprotein complextherapeutic target
项目摘要
DESCRIPTION (provided by applicant): This is an application for a Mentored Clinical Scientist Research Career Development Award (K08) for Michael LaFemina, MD, an Instructor in the Department of Medicine, Division of Pulmonary and Critical Care, at the University of California, San Francisco. Dr. LaFemina is establishing himself as a young investigator in the field of alveolar epithelial biology relating to acute lung injury. Specifically, this application s focused on the role of alveolar epithelial barrier disruption in the pathogenesis of acute lung injury1. Despite the requirement to strictly control barrier function in the alveolar epithelium2, ittle is known about the nature of tight junctions in the lung. Claudins are a family of transmembrane proteins that are both necessary and sufficient for tight junction formation3. Claudin-18, the only
lung-specific tight junction protein4, is the most highly expressed claudin in type 1 pneumocytes5, suggesting a lung-specific function. Preliminary data indicate that (1) mice deficient in claudin-18 have increased alveolar permeability to albumin and the specific knockdown of claudin-18 in primary alveolar epithelial cells induces hyperpermeability; (2) claudin-18 null mice develop lung injury in the postnatal period, progressive fibrosis, and transforming growth factor-? (TGF?) activation; and (3) inflammation induces a specific loss of claudin-18 associated with increased permeability. Based on this preliminary data, the overall objective of this application is to elucidate the function of claudin-18 and to determine the role f this tight junction protein in the pathogenesis of acute lung injury. Aim 1 will test the hypothesi that claudin-18 is a unique paracellular barrier to macromolecules though studies of lung fluid balance in a novel claudin-18 deficient mouse and barrier function in primary alveolar epithelial cells deficient in claudin-18. Aim 2 will determine the mechanism of lung injury in the setting of claudin-18 deficiency and will investigate the link between barrier dysfunction, lung injury, and TGF-? activation. Aim 3 will determine the role of claudin-18 in clinically relevant models of acute lung injury through studies in ex vivo perfused human lung preparations. Dr. LaFemina's career development during this award will be organized around these aims and guided by formal mentorship and coursework. Dr. LaFemina has assembled a multidisciplinary team of UCSF senior investigators to mentor him: Dean Sheppard, MD, Professor of Medicine and an expert in integrin mediated activation of TGF-?; James Frank, MD, Associate Professor of Medicine and an expert in basic mechanisms of acute lung injury and tight junction biology; and Michael Matthay, MD, Professor of Medicine and Anesthesia and expert investigator in the basic and clinical science of acute lung injury. Dr. LaFemina's research proposal focusing on the novel protein claudin-18 coupled with his structured training plan will allow him to accomplish his
long term goal career goal of becoming an independently funded physician scientist improving patient health through the study of basic mechanisms of alveolar epithelial biology. Disruption of the barrier between air and blood in the lung can lead to respiratory failure and death. Tight junctions are protein complexes that regulate this barrier. This study will investigate the role of
the tight junction protein claudin-18 in lung injury and will determine whether this protein is a potential therapeutic target.
描述(由申请人提供):这是为Michael LaFemina医学博士申请临床科学家研究生涯发展奖(K08)的申请书,Michael LaFemina是加州大学旧金山分校肺科和重症监护科医学部的讲师。拉菲米纳博士在与急性肺损伤相关的肺泡上皮生物学领域确立了自己作为年轻研究员的地位。具体地说,S的应用集中在肺泡上皮屏障破坏在急性肺损伤发病机制中的作用1。尽管要求严格控制肺泡上皮细胞的屏障功能,但人们对肺内紧密连接的本质知之甚少。Claudins是一个跨膜蛋白家族,对紧密连接的形成既是必要的,也是充分的。克拉丁-18,唯一的
肺特异性紧密连接蛋白4是在1型肺细胞中表达最高的Claudin,提示肺特有的功能。初步研究结果表明:(1)claudin-18基因缺陷小鼠肺泡对白蛋白的通透性增加,而原代肺泡上皮细胞中claudin-18基因的特异性敲除导致高通透性;(2)claudin-18基因缺失小鼠在出生后出现肺损伤、进行性纤维化和转化生长因子?(转化生长因子?)激活;(3)炎症导致与通透性增加相关的claudin-18的特异性丢失。基于这些初步数据,这项应用的总体目标是阐明claudin-18的功能,并确定这一紧密连接蛋白在急性肺损伤发病机制中的作用。目的1通过对Claudin-18基因缺陷小鼠的肺液平衡和原代肺泡上皮细胞的屏障功能的研究,验证Claudin-18是一种独特的大分子细胞旁屏障的假设。目的2将确定claudin-18缺乏时肺损伤的机制,并将探讨屏障功能障碍、肺损伤和转化生长因子?激活。目的3通过对体外人肺灌流标本的研究,确定Claudin-18在临床相关急性肺损伤模型中的作用。LaFemina博士在该奖项期间的职业发展将围绕这些目标进行组织,并以正式的指导和课程工作为指导。LaFemina博士组建了一个由加州大学旧金山分校高级研究人员组成的多学科团队来指导他:医学博士、医学教授和整合素介导的转化生长因子-?激活专家谢泼德;医学副教授、急性肺损伤基本机制和紧密连接生物学专家詹姆斯·弗兰克;医学博士迈克尔·马泰,医学和麻醉学教授,急性肺损伤基础和临床科学专家研究员。LaFemina博士专注于新型蛋白质claudin-18的研究提案,加上他的结构化训练计划,将使他能够完成他的
长期目标是成为一名独立资助的内科科学家,通过研究肺泡上皮生物学的基本机制来改善患者的健康。破坏肺内空气和血液之间的屏障可导致呼吸衰竭和死亡。紧密连接是调节这一屏障的蛋白质复合体。这项研究将调查
紧密连接蛋白claudin-18在肺损伤中的作用,并将确定该蛋白是否为潜在的治疗靶点。
项目成果
期刊论文数量(0)
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Michael Joseph LaFemina其他文献
Michael Joseph LaFemina的其他文献
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{{ truncateString('Michael Joseph LaFemina', 18)}}的其他基金
Claudin-18 and pathologic alveolar epithelial permeability
Claudin-18 和病理性肺泡上皮通透性
- 批准号:
8613503 - 财政年份:2013
- 资助金额:
$ 13.23万 - 项目类别:
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