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Effects of shear stress on regulation of epithelial permeability

剪切应力对上皮通透性调节的影响

基本信息

批准号：
8292032
负责人：
Venkataramana K Sidhaye
金额：
$ 13.55万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-03 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8292032
关键词：
Actins Air Apical Area Asthma Breathing Calcium Cations Cells Coughing Critical Care Cytoskeleton DNA Sequence Rearrangement Data Development Disease Endothelial Cells Environment Environmental air flow Epidermal Growth Factor Epithelial Epithelial Cells Event Exercise Foundations Frequencies Goals Height Hepatocyte Human Infection Inflammation Ion Channel Kidney L-Type Calcium Channels Lung Mechanics Medicine Membrane Metabolic acidosis MicroRNAs Modeling Mus Nifedipine Nitric Oxide Organ Pathologic Pathway interactions Permeability Physiological Physiology Play Production Property Proteins Regulation Relative (related person)Reporting Research Personnel Respiration Respiratory physiology Rest Role Signal Transduction Source Stimulus Structure of respiratory epithelium Surface TRPV channel Techniques Tidal Volume Tight Junctions Trachea Tubular formation Vanilloid Vascular Endothelial Cell Water airway epithelium airway surface liquid aquaporin 5 career claudin-1 protein cytokine experience genetic manipulation human NOS3 protein in vitro Model inhibitor/antagonist interest novel particle programs receptor release of sequestered calcium ion into cytoplasm response shear stress skills tool voltage gated channel water channel

项目摘要

The goal of this K08 application is to facilitate development of essential skills that will allow the PI to become a successful academician and achieve independent scientific investigator status. The respiratory epithelium serves as a barrier, a regulator of the content of airway surface liquid, and a source of cytokines and other products that regulate airway physiology. In addition to cyclic extensions and contraction, airway epithelial cells are exposed to lumenal shear stress, defined as the frictional force per unit surface area, generated by airflow. The shear stress sensed by airway epithelia is continuously changing under both physiologic and pathologic conditions. We have exciting novel data suggesting that shear stress in airway epithelial cells leads to changes in airway epithelial permeability. Therefore, dynamic modulation of the airway epithelial barrier could be an important mechanism by which epithelial cells transduce lumenal information into subepithelial responses. Our preliminary studies indicate that shear stress induces TRPV4 activation with subsequent L-type voltage gated channel activation with subsequent increases in intracellular calcium. The increase in intracellular calcium in airway epithelial cells leads to concerted changes in epithelial paracellular permeability by modulating actin rearrangement and NO production, as well as in transmembrane permeability by modulating AQP5 abundance. We propose to study the role of shear stress in altering both paracellular and transmembrane permeability as well as dissect the underlying mechanisms regulating these effects. In SA#1we will investigate the effects of shear stress on airway epithelial permeability using primary cultured human airway epithelial cells (NHBE) and.ex vivo isolated mouse trachea. In SA#2 we will define the role for and the mechanisms (TRPV4, L-type channel) of shear-induced calcium flux in modulating epithelial permeability using pharmacologic inhibition and genetic manipulation. In SA#3 we will study the role od shear-induced increases in calcium on NO production and its effect on permeability. Through these complimentary techniques and coursework, the PI will develop new skills and generate novel data regarding the effects of mechanical shear stress on airway epithelial cell regulation and function, a little-examined area likely to be of immense importance to normal lung function, as well as conditions of altered shear including exercise and asthma.

此K08应用程序的目标是促进基本技能的发展，使PI成为成为一名成功的院士，并获得独立的科学研究者地位。呼吸上皮作为屏障、气道表面液体含量的调节剂以及细胞因子和其他细胞因子的来源，调节气道生理的产品。除了周期性伸展和收缩，气道上皮细胞细胞暴露于由以下因素产生的腔内切应力（定义为每单位表面积的摩擦力）气流由气道上皮感觉到的剪切应力在生理和生理条件下都是连续变化的。病理条件。我们有令人兴奋的新数据表明，气道上皮细胞中的切应力导致气道上皮通透性的变化。因此，气道上皮细胞的动态调节屏障可能是上皮细胞将管腔信息传递到上皮下反应我们的初步研究表明，剪切应力诱导TRPV 4活化，随后的L型电压门控通道激活，随后细胞内钙增加。的气道上皮细胞内钙离子的增加导致上皮细胞旁钙离子的协同变化，通过调节肌动蛋白重排和NO的产生，以及跨膜通过调节AQP5丰度来增加渗透性。我们建议研究剪切应力在改变这两个方面的作用，细胞旁和跨膜渗透性，以及解剖的基本机制，调节这些方面的影响.在SA#1中，我们将使用原发性支气管肺泡灌洗液研究切应力对气道上皮通透性的影响。培养的人气道上皮细胞（NHBE）和离体分离的小鼠气管。在SA#2中，我们将定义剪切诱导的钙流在调节心肌细胞凋亡中的作用及其机制（TRPV4，L型通道）通过药理学抑制和遗传操作来检测上皮渗透性。在SA#3中，我们将研究剪切诱导的钙增加对NO产生的作用及其对渗透性的影响。通过这些免费的技术和课程，PI将开发新的技能，并产生新的数据，机械切应力对气道上皮细胞调节和功能的影响，这是一个很少研究的领域可能对正常肺功能以及剪切力改变的情况非常重要，运动和哮喘

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mucosal expression of aquaporin 5 and epithelial barrier proteins in chronic rhinosinusitis with and without nasal polyps.

DOI：
10.1016/j.amjoto.2013.11.011
发表时间：
2014-05
期刊：
American journal of otolaryngology
影响因子：
2.5
作者：
Shikani AH;Sidhaye VK;Basaraba RJ;Shikani HJ;Alqudah MA;Kirk N;Cope E;Leid JG
通讯作者：
Leid JG

Epidermal aquaporin-3 is increased in the cutaneous burn wound.