TNF-a Induced Increase in Alveolar Epithelial Cell Stiffness Increase and Lung In

TNF-a 诱导肺泡上皮细胞硬度增加和肺损伤

• 批准号: 8616202
• 负责人: ESRA ROAN
• 金额: $ 14.62万
• 依托单位: UNIVERSITY OF MEMPHIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8616202
• 关键词: Actins; Acute Lung Injury; Address; Adhesions; Adult Respiratory Distress Syndrome; Air; Alveolar; Alveolus; Animal Model; Animals; Award; Biochemical; Biology; Biomedical Research; Biophysical Process; Cells; Clinical; Clinical Research; Complex; Computer Simulation; Cytoskeletal Proteins; Cytoskeleton; Development; Disease; Early Diagnosis; Edema; Elements; Environment; Epithelial; Epithelial Cells; Exposure to; Fluorescence Microscopy; Functional disorder; Genistein; Goals; Health; Health Sciences; Hour; Immunology; Inflammation Mediators; Inflammatory; Injury; Institution; Intercellular Junctions; JUN gene; Knowledge; Lead; Length; Liquid substance; Lung; MAP Kinase Gene; MAPK8 gene; Maps; Measurement; Measures; Mechanical ventilation; Mechanics; Mediating; Mentors; Modeling; Nature; Organizational Change; Outcome; Patients; Permeability; Phosphorylation; Phosphotransferases; Phosphotyrosine; Physiology; Process; Proteins; Research; Research Personnel; Resolution; Role; Scanning Probe Microscopes; Small Interfering RNA; Stimulus; Stress; Stretching; Structure; TNF gene; Tennessee; Tidal Volume; Tight Junctions; Tissues; Training Activity; Tumor Necrosis Factor-alpha; Tyrosine Phosphorylation; Universities; Ventilator-induced lung injury; Water; career; career development; cell injury; cytokine; experience; in vivo; inhibitor/antagonist; laboratory facility; link protein; lung injury; occludin; polymerization; professor; programs; repaired; research and development; respiratory; response; soft tissue; sound

DESCRIPTION (provided by applicant): The goal of this K01 Mentored Career Award application is to advance Dr. Roan's career through research experiences, scholarly activities, training, and collaborative efforts. This will enable her to establish a sound Biomedical Research Program in Lung Health and Physiology at the University of Memphis (U of M), a diverse institution in an urban environment. More specifically, Dr. Roan will develop expertise in lung physiology and air-fluid barrier functionality through a robust set of activities that investigate alveolar permeability that will enable transition from an investigator with a background in soft tissue mechanics and mechanobiology to an independent researcher focused on acute lung injury. The proposed research focuses on acute respiratory distress syndrome, a devastating condition characterized in part by the presence of protein rich edema in the alveolar airspaces. Because clearance of edema is critical to resolution of the disease, strategies directed toward protecting the epithelial barrier and promoting epithelial repair are needed. The central hypothesis is that tumor necrosis factor-α (TNF-α) induces an increase in cytoskeletal tension within the alveolar epithelial cells making them more susceptible to barrier dysfunction and cell detachment caused by stretch through c-Jun NH2 kinase- (JNK-) mediated phosphorylation of zonula occludens 1 (ZO-1). In Aim 1, Dr. Roan will show that TNF-α and stretch will lead to much more cell detachment than either stimulus alone due to an increase in cell stiffness. Aim 2 will show that the increase in stiffness and barrier dysfunction are dependent on ZO-1 phosphorylation through JNK. In Aim 3, a multi- scale finite element model will be developed to predict how changes in junctional stress caused by TNF-α can lead to increased barrier dysfunction in vivo. Overall, this project will elucidate how early exposure of alveolar epithelial cells to TNF-α prior to mechanical ventilation induces cytoskeletal remodeling and alters the biophysical forces at the tight junctions leading to more injury. The candidate will be mentored by well- established investigators, with Dr. C.M. Waters, Professor and Vice Chair, Physiology, University of Tennessee Health Science Center (UTHSC) serving as the lead mentor. Dr. R.K. Rao and Dr. E. Fitzpatrick will guide the tight-junction biology and immunology aspects, respectively. Training activities will take place at both the University of Memphis and the UTHSC, partner institutions separated by an approximately 10 minute drive and synergistically pursuing biomedical research through a range of inter-campus activities. The UofM has agreed to allocate 75% of Dr. Roan's effort, and both the UofM and the UTHSC have agreed to provide access to curricular and laboratory facilities as needed to carry out the proposed 5-year mentored research and career development project for Dr. Roan to advance her career and establish a sound research program here at the U of M.

描述（由应用程序提供）：该K01指导职业奖的目标的目的是通过研究经验，科学活动，培训和协作努力来推动Roan博士的职业生涯。这将使她能够在孟菲斯大学（U Of M）建立一个合理的生物医学研究计划，该计划是城市环境中的潜水机构。更具体地说，Roan博士将通过一组强大的活动来开发肺部生理学和空气屏障功能方面的专业知识，这些活动研究肺泡通透性，这将使从具有软组织机械和机制背景的研究者过渡到针对急性肺部受伤的独立研究人员。拟议的研究集中于急性呼吸窘迫综合征，这是一种毁灭性疾病，部分原因是肺泡空体中存在富含蛋白质的水肿。由于水肿清除对于解决疾病至关重要，因此需要针对保护上皮屏障和促进上皮修复的策略。 The central hypothesis is that tumor necrosis factor-α (TNF-α) induces an increase in cytoskeletal tension within the alveolar epithelial cells making them more susceptible to barrier dysfunction and cell detachment caused by stretch through c-Jun NH2 kinase- (JNK-) mediated phosphorylation of zonula occludens 1 (ZO-1).在AIM 1中，Roan博士将表明，由于细胞刚度的增加，TNF-α和拉伸将导致细胞脱离比单独刺激的细胞脱离更多。 AIM 2将表明刚度和屏障功能障碍的增加取决于通过JNK的ZO-1磷酸化。在AIM 3中，将开发多尺度有限元模型，以预测由TNF-α引起的连接应力变化如何导致体内屏障功能障碍的增加。总体而言，该项目将阐明肺泡上皮细胞在机械通气之前向TNF-α的早期暴露如何诱导细胞骨架重塑，并在紧密连接处改变生物物理力，从而导致更多损伤。候选人将由良好的调查员与C.M.博士一起考虑。田纳西大学健康科学中心（UTHSC）生理学教授兼副主席沃特斯（Waters）担任首席导师。 R.K.博士Rao和E. Fitzpatrick博士将分别指导生物学和免疫学方面。培训活动将在孟菲斯大学和UTHSC，合作伙伴机构进行大约10分钟的车程，并通过一系列校园间活动进行生物医学研究。 UOFM已同意分配Roan博士的75％的努力，UOFM和UTHSC都同意根据需要提供访问课程和实验室设施的访问权限，以为Roan博士提供拟议的5年指导研究和职业发展项目，以促进她的职业生涯，并在M中建立一项合理的研究计划。