The Role of 2-Pore Domain Potassium Channels in Acute Lung Injury.

2 孔域钾通道在急性肺损伤中的作用。

基本信息

批准号：
9272423
负责人：
Andreas Schwingshackl
金额：
$ 17.39万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9272423
关键词：
Acute Lung Injury Advisory Committees Affect Alveolar Award Bronchoalveolar Lavage Fluid Budgets Clinical Collaborations Coupling Development Disease Dyes Electrical Resistance Electrophysiology (science)Environment Environmental air flow Epithelial Epithelial Cell Proliferation Epithelial Cells Evans blue stain Exposure to Financial Support Functional disorder Funding Goals Healthcare Human Hyperoxia Image Immunohistochemistry In Vitro Inflammation Mediators Inflammatory Intensive Care International Intervention Knockout Mice Life Literature Lung Measurement Measures Mechanical ventilation Mechanics Medicine Mentorship Molecular Morbidity - disease rate Mus Outcome Oxygen Oxygen Therapy Care Pathogenesis Pathogenicity Pathway interactions Patients Permeability Phosphorylation Potassium Potassium Channel Protein Isoforms Proteins Publications Pulmonology Rattus Regulation Reporting Research Research Infrastructure Role Savings Signal Transduction Slice Speed Stimulus Stretching TNF gene Techniques Therapeutic Therapeutic Intervention Tight Junctions Transducers Water base career cytokine electric impedance experimental study improved in vivo in vivo Model inhibitor/antagonist innovation interest knock-down lung injury mechanotransduction meetings monolayer mortality new therapeutic target novel novel therapeutic intervention overexpression patch clamp pressure public health relevance response sensor success treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Despite advances in Pulmonology and Intensive Care Medicine, mortality rates of patients with Acute Lung Injury (ALI) remain high, perhaps because the underlying mechanisms of this disease are poorly understood. Patients with ALI routinely require high oxygen concentrations and positive-pressure ventilation, although both therapies accentuate ongoing lung injury. While the signaling cascades activated by hyperoxia are well known, "mechano-transduction" after alveolar distension is poorly understood. Recent literature suggests that 2-pore domain potassium (K2P) channels may act as mechano-sensors and mechano-transducers, and participate in stimulus-secretion coupling. However, little is known about the expression and potential functions of K2P channels in the lung. We propose a bold and novel hypothesis that K2P channels are expressed in lung epithelial cells, and that pathogenic K2P channel regulation caused by hyperoxia, mechanical stretch and TNF-a exposure, an environment similar to the one encountered in ALI, results in dysregulation of inflammatory mediator secretion from epithelial cells, and in loss of epithelial barrier function, two hallmarks of ALI. Our overarching objective is to investigate the mechanisms leading to hyperoxia- and mechanical stretch- induced lung injury, and to identify K2P channels as a new target in the search for innovative therapeutic strategies against ALI. Specifically, we will use both in vitro and in vivo approaches including K2P knockout mice to [1] investigate the effects of hyperoxia, mechanical stretch and TNF-a on K2P channel expression and function in cultured mouse and primary rat and human alveolar epithelial cells using molecular techniques, immunohistochemistry and patch clamp studies, [2] to determine the role of K2P channels in inflammatory mediator secretion from cultured and primary alveolar epithelial cells, and in broncho-alveolar lavage fluid from K2P knockout mice, and [3] to demonstrate that K2P channels regulate epithelial barrier function via Ca2+-dependent tight junction phosphorylation. We have the unique expertise and technical capabilities to study the effects of hyperoxia and mechanical stretch in both in vitro and in vivo models of ALI. In addition, Dr. Jaggar has an inimitable setup to measure global and localized intracellular Ca2+ concentrations. The academic environment at UTHSC, the outstanding mentorship, rich opportunities for collaborations, and the institutional, departmental, and divisional commitment to my research success provide the intellectual infrastructure and the financial support to guarantee my progress towards independent research funding, including an R01 award, within 5 years. These long-term goals will be achieved by targeting a minimum of 2 publications and 2 abstract presentations per year at international meetings, supplemented by formal coursework, and the close mentorship of Dr. Waters, Dr. Anand and my Career Advisory Committee.

描述（由申请人提供）：尽管肺功率和重症监护医学的进展，急性肺损伤患者的死亡率（ALI）仍然很高，也许是因为该疾病的潜在机制知之甚少。尽管两种疗法都会突出持续的肺损伤，但患有ALI的患者通常需要高氧浓度和正压通风。虽然高氧激活的信号传导级联反应是众所周知的，但肺泡延伸后的“机械转移”知之甚少。最近的文献表明，2孔域钾（K2P）通道可以充当机械传感器和机械转换器，并参与刺激 - 分泌耦合。但是，关于肺中K2P通道的表达和潜在功能知之甚少。 We propose a bold and novel hypothesis that K2P channels are expressed in lung epithelial cells, and that pathogenic K2P channel regulation caused by hyperoxia, mechanical stretch and TNF-a exposure, an environment similar to the one encountered in ALI, results in dysregulation of inflammatory mediator secretion from epithelial cells, and in loss of epithelial barrier function, two hallmarks of ALI.我们的总体目标是研究导致高氧和机械拉伸诱发肺损伤的机制，并确定K2P通道是寻找针对ALI的创新治疗策略的新目标。具体而言，我们将同时使用包括K2P敲除小鼠在内的体外和体内方法[1]研究高氧，机械拉伸和TNF-A对K2P通道表达和功能在培养的小鼠以及原发性大鼠以及人肺泡上皮细胞中的作用，并使用分子技术，使用免疫组织和斑块层培养剂，[2]的作用[2]肺泡上皮细胞，以及来自K2P敲除小鼠的支气管 - 肺泡灌洗液，[3]证明K2P通道通过CA2+依赖性紧密的连接磷酸化调节上皮屏障功能。我们具有独特的专业知识和技术能力，可以研究体外和体内ALI模型中高氧和机械伸展的影响。此外，Jaggar博士还具有无与伦比的设置，可以测量全球和局部的细胞内Ca2+浓度。 UTHSC的学术环境，杰出的指导，丰富的合作机会以及对我的研究成功的机构，部门和部门承诺提供了智力基础设施和财务支持，以确保我在5年内取得了独立研究资金的进步，包括R01奖。这些长期目标将通过针对国际会议上的每年至少2个出版物和2个摘要演讲来实现，并在正式课程中得到补充，以及沃特斯博士，Anand博士和我的职业咨询委员会的密切指导。