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：
8224617
负责人：
Charles Corey Hardin
金额：
$ 15.3万
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 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8224617
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

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 医学博士、哲学博士是马萨诸塞州总医院肺科和重症监护医学科以及哈佛大学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科和重症监护科的一名主治医师。他拥有生物物理学以及肺科和重症监护医学背景。他的博士研究重点是玻璃状生物材料的统计力学，而博士后研究的重点是细胞骨架的动力学。他是五篇第一作者论文的作者。他最近的工作正在接受审查，他是该工作的共同第一作者，描述了在细胞单层中首次直接测量细胞-细胞连接处细胞间力的分布[1]。在此进展的基础上，在目前的 K25 应用中，他将测试以下假设：肺内皮细胞细胞骨架的内在机械特性是这些细胞间力分布的主要决定因素。他还将测试两个推论假设：1）这些机械特性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发生变化，2）这种变化会损害内皮屏障功能。作为一项实验细胞生物学研究，这项工作标志着哈丁博士在理论物理学方面的研究生工作的不同。因此，受指导的 K25 将提供持续培训和研究所需的支持。最终，这笔职业发展补助金将为哈丁博士成为一名成功的独立研究者奠定基础。环境： Jeffrey Fredberg 教授将担任 Hardin 博士的主要导师。 Fredberg 教授是一位著名的肺生理学家，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生和博士后实习生的主要导师。在完成培训的人中，有九人成为独立首席研究员，七人获得了终身教职，六人成为正教授。他还是最近更新的跨学科肺科学 T32 培训补助金和 2 项新的 RO1 补助金的 PI。他的实验室的跨学科工作受到广泛关注[2-5]。 Hardin 博士还将与 Fredberg 教授保持着密切联系的其他杰出生理学家和临床医生进行密切合作，其中包括 James P. Butler 博士和 Atul Malhotra 博士。哈佛公共卫生学院毗邻麻省总医院、布莱根妇女医院、哈佛医学院，提供了优良的智力环境。 Hardin 博士还将在马萨诸塞州总医院任命一名工作人员，在那里他将与 Taylor Thompson 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]，其发生主要是由于内皮细胞之间间隙的形成[8]。现在人们对信号级联和所涉及的生物介质了解很多，但对潜在的细胞骨架和机械事件知之甚少。我和我的同事最近开发的一项技术（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，发现细胞令人惊讶的物理特性，包括细胞牵引力（傅里叶变换牵引显微镜或 FTTC[9, 10]）和细胞骨架力学（光磁扭转细胞仪 OMTC[11-15] 和细胞）映射流变测定法[12, 16]），我们现在能够全面表征肺内皮单层的力学及其疾病模型的改变。