Cell Mechanical Aspects of the Acute Respiratory Distress Syndrome

急性呼吸窘迫综合征的细胞机械方面

• 批准号: 8588349
• 负责人: Charles Corey Hardin
• 金额: $ 13.86万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-15 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588349
• 关键词: Acute; Acute Lung Injury; Adhesives; Adult Respiratory Distress Syndrome; Affect; Aftercare; Appointment; Area; Asthma; Behavior; Biocompatible Materials; Biological; Biology; Cells; Cellular Stress; Cellular biology; Collaborations; Colloids; Critical Care; Cytometry; Cytoskeleton; Dependence; Disease model; Doctor of Philosophy; Endothelial Cells; Endothelium; Environment; Equilibrium; Event; Foundations; Fourier Transform; General Hospitals; Global Change; Goals; Grant; Histamine; Homeostasis; Hospitals; Human; Individual; Inflammatory; Injury; Intercellular Junctions; Intervention; Investigation; Laboratories; Link; Literature; Lung; Magnetism; Maps; Massachusetts; Measurement; Measures; Mechanics; Mediator of activation protein; Medicine; Mentors; Methodology; Microscopy; Modeling; Molecular; Optics; Paper; Pathology; Permeability; Physicians; Physics; Physiological; Physiology; Population; Population Decreases; Positioning Attribute; Postdoctoral Fellow; Principal Investigator; Property; Public Health Schools; Pulmonary Edema; Rattus; Research; Research Personnel; Research Training; Role; Science; Seminal; Signal Transduction; Statistical Mechanics; Stress; Stretching; Sum; Tail; Techniques; Testing; Thinking; Time; Traction; Training; Ursidae Family; Vascular Permeabilities; Woman; Work; career development; medical schools; monolayer; mortality; novel; particle; physical property; predictive modeling; professor; programs; research study; sphingosine 1-phosphate; theories; therapeutic target; transmission process

DESCRIPTION (provided by applicant): Charles Corey Hardin MD, PhD is a fellow both in the Division of Pulmonary and Critical Care Medicine at Massachusetts General Hospital and in the Molecular and Integrative Physiology Program at the Harvard School of Public Health. He will become a staff physician in the Pulmonary and Critical Care Division at Massachusetts General Hospital in July of 2011. He has a background in biological physics and pulmonary and critical care medicine. His doctoral research focused on statistical mechanics of glassy biological materials, while his post-doctoral research focuses on dynamics of the cytoskeleton. He is the author of five first-author papers. His most recent work, which is in review, and on which he is co-first author, describes the first direct measurement in cellular monolayers of the distribution of intercellular forces at cell-cell junctions[1]. Building on that advance, in the prsent K25 application he will test the hypothesis that the intrinsic mechanical properties of the cytoskeleton in pulmonary endothelial cells are major determinants of the distribution of these intercellular forces. He will also test the two corollary hypotheses that 1) these mechanical properties change in predictable ways in models of acute lung injury and the Acute Respiratory Distress Syndrome (ARDS), and 2) that such changes compromise endothelial barrier function. As a study in experimental cellular biology, this work marks a departure from Dr. Hardin's graduate work in theoretical physics. As such, a mentored K25 will provide the support necessary to pursue ongoing training and research. Ultimately, this career development grant will form the foundation upon which Dr. Hardin will become a successful independent investigator. Environment: Prof. Jeffrey Fredberg will serve as Dr. Hardin's primary mentor. Prof. Fredberg is a renowned pulmonary physiologist who has made seminal contributions to the study of asthma and, more recently, to the experimental study of cell mechanics more broadly. He has an excellent track record in training new investigators, having served as primary mentor for 41 past and present doctoral and post-doctoral trainees. Of those who have completed their training, nine have gone on to become independent principal investigators, seven have earned tenure and six are full professors. He is also PI of a recently renewed T32 training grant in interdisciplinary pulmonary sciences and 2 new RO1 grants. The interdisciplinary work from his laboratory has been widely noted[2-5]. Dr. Hardin will also enjoy close collaborations with other eminent physiologists and clinicians with whom Prof. Fredberg maintains close ties including Dr. James P. Butler and Dr. Atul Malhotra. The Harvard School of Public Health is in close proximity to the Massachusetts General Hospital, Brigham and Women's Hospital, and Harvard Medical School, thus providing an excellent intellectual environment. Dr. Hardin will also have a staff appointment at the Massachusetts General Hospital, where he will enjoy close collaboration with experts in ARDS such as Dr. Taylor Thompson. Research: ARDS is a major cause of mortality[6]. Among the earliest events in the pathology of ARDS is the breakdown of the endothelial barrier[7], which occurs primarily because of the formation of gaps between endothelial cells[8]. A great amount is now known about the signaling cascades and biologic mediators involved, but far less is known about underlying cytoskeletal and mechanical events. A technique recently developed my colleagues and I (Monolayer Stress Microscopy or MSM) allows for the first time direct measurement of intercellular forces[1]. Combined with methodologies already invented in our lab to discover the surprising physical properties of the cell including cellular traction forces (Fourier Transform Traction Microscopy or FTTC[9, 10]) and cytoskeletal mechanics (Optical Magnetic Twisting Cytometry OMTC[11-15] and Cell Mapping Rheometry[12, 16]), we are now in a position to characterize comprehensively the mechanics of the pulmonary endothelial monolayer and its alteration in models of disease.

描述（由申请人提供）：Charles Corey哈丁医学博士，博士是马萨诸塞州总医院肺部和重症监护医学科以及哈佛公共卫生学院分子和综合生理学项目的研究员。他将于2011年7月成为马萨诸塞州总医院肺部和重症监护科的一名医生。他有生物物理学和肺部及重症监护医学的背景。他的博士研究主要集中在玻璃生物材料的统计力学，而他的博士后研究主要集中在细胞骨架的动力学。他是五篇第一作者论文的作者。他最近的工作，这是在审查中，他是共同第一作者，描述了在细胞单层的细胞间力的分布在细胞连接的第一个直接测量[1]。在这一进展的基础上，在目前的K25应用中，他将测试肺内皮细胞中细胞骨架的内在力学性质是这些细胞间力分布的主要决定因素的假设。他还将测试两个推论假设：1）这些机械性能在急性肺损伤和急性呼吸窘迫综合征（ARDS）模型中以可预测的方式变化，以及2）这些变化损害内皮屏障功能。作为实验细胞生物学的研究，这项工作标志着哈丁博士在理论物理学研究生工作的出发点。因此，一个辅导K25将提供必要的支持，继续进行培训和研究。最终，这项职业发展补助金将成为哈丁博士成为一名成功的独立调查员的基础。环境：杰弗里·弗雷德伯格教授将担任哈丁博士的主要导师。Fredberg教授是一位著名的肺部生理学家，他对哮喘研究以及最近更广泛的细胞力学实验研究做出了开创性贡献。他在培训新的研究人员方面有着出色的记录，曾担任41名过去和现在的博士和博士后学员的主要导师。在完成培训的人中，有9人成为独立的主要调查员，7人获得终身职位，6人成为正教授。他还是最近更新的T32跨学科肺科学培训补助金和2个新的RO 1赠款的PI。他的实验室的跨学科工作已被广泛注意到[2-5]。哈丁博士还将与其他著名的生理学家和临床医生密切合作，Fredberg教授与他们保持密切联系，包括James P. Butler博士和Atul Malhotra博士。哈佛公共卫生学院靠近马萨诸塞州总医院、布里格姆妇女医院和哈佛医学院，因此提供了一个极好的智力环境。哈丁博士还将在马萨诸塞州总医院担任工作人员，在那里他将与泰勒·汤普森博士等ARDS专家密切合作。研究：ARDS是死亡的主要原因[6]。ARDS病理学中最早的事件之一是内皮屏障的破坏[7]，其主要是由于内皮细胞之间形成间隙而发生[8]。大量的是现在已知的信号级联和生物介质参与，但少得多的是了解潜在的细胞骨架和机械事件。我和同事最近开发的一种技术（单层应力显微镜或MSM）首次允许直接测量细胞间力[1]。结合我们实验室已经发明的方法来发现细胞的惊人物理特性，包括细胞牵引力（傅立叶变换牵引显微镜或FTTC[9，10]）和细胞骨架力学（光磁扭转细胞计数OMTC[11-15]和细胞绘图流变测定[12，16]），我们现在能够全面地表征肺内皮单层的力学及其在疾病模型中的改变。