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

基本信息

批准号：
8776968
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
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-12-15 至 2015-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8776968
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 Monolayer Stress Microscopy 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

项目摘要

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 Hardin MD博士是马萨诸塞州综合医院的肺和重症监护医学部以及哈佛大学公共卫生学院的分子和综合生理学计划。他将于2011年7月成为马萨诸塞州综合医院肺和重症监护室的工作人员。他的博士研究重点是玻璃生物材料的统计力学，而他的博士后研究则集中于细胞骨架的动力学。他是五篇第一作者论文的作者。他的最新工作正在审查中，他是他的第一作者，描述了细胞单层的第一个直接测量，即细胞 - 细胞连接处细胞间力分布的分布[1]。在这一进步的基础上，在PRSENT K25应用中，他将检验以下假设：肺内皮细胞中细胞骨架的内在机械性能是这些细胞间力分布的主要决定因素。他还将检验两个推论假设，即1）这些机械性能在急性肺损伤模型和急性呼吸遇险综合征（ARDS）的模型中可预测的方式变化，以及2）这种改变的内皮障碍功能。作为实验性细胞生物学的研究，这项工作标志着哈丁博士在理论物理学领域的研究生工作。因此，指导的K25将为进行持续的培训和研究提供必要的支持。最终，这项职业发展赠款将构成Hardin博士成为成功的独立调查员的基础。环境：Jeffrey Fredberg教授将担任Hardin博士的主要导师。弗雷德伯格（Fredberg）教授是一位著名的肺部生理学家，他对哮喘的研究做出了开创性的贡献，最近对细胞力学的实验研究做出了更广泛的贡献。他在培训新调查员方面拥有出色的往绩，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，有九名已经成为独立的首席调查员，七名获得了任期，六名是全部教授。他还是最近在跨学科肺科学和2个新的RO1补助金的T32培训赠款的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杰出的生理学家和临床医生进行密切合作，弗雷德伯格教授与詹姆斯·P·巴特勒博士和阿图尔·马尔霍特拉博士保持紧密联系。哈佛大学公共卫生学院靠近马萨诸塞州综合医院，杨百翰和妇女医院以及哈佛医学院，从而提供了极好的智力环境。哈丁博士还将在马萨诸塞州综合医院任职，他将与泰勒·汤普森（Taylor Thompson）博士等ARDS的专家进行密切合作。研究：ARDS是死亡率的主要原因[6]。 ARDS病理中最早的事件是内皮屏障的分解[7]，这主要是由于内皮细胞之间的间隙形成[8]。现在已经知道有关涉及的信号传导级联和生物学介质的知识，但对潜在的细胞骨架和机械事件的了解众所周知。最近开发了我的同事和I（单层应力显微镜或MSM）的技术首次直接测量细胞间力[1]。结合我们实验室已经发明的方法，以发现细胞的物理特性，包括细胞牵引力（傅立叶变换牵引力显微镜或FTTC [9，10]）和细胞骨架力学（光学磁性扭曲细胞测量量OMTC [11-15]和细胞映射rheotilime [12，16]），我们现在是一个特征性的机制，即在某些机构中构成特征的特征。单层及其在疾病模型中的改变。