Cell Mechanical Aspects of the Acute Respiratory Distress Syndrome

简介(申请人提供)：查尔斯·科里·哈丁，医学博士，麻省总医院肺部和重症监护医学部研究员，哈佛大学公共卫生学院分子和综合生理学项目研究员。他将于2011年7月成为马萨诸塞州综合医院肺部和重症监护科的一名专职医生。他有生物物理学和肺部及重症监护医学的背景。他的博士研究重点是玻璃生物材料的统计力学，而他的博士后研究重点是细胞骨架的动力学。他是五篇第一作者论文的作者。他的最新工作正在审查中，他是第一作者之一，描述了第一次在细胞单层中直接测量细胞-细胞连接处的细胞间力分布[1]。在这一进展的基础上，在目前的K25应用中，他将测试这一假设，即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：1)在急性肺损伤和急性呼吸窘迫综合征(ARDS)模型中，这些机械性能以可预测的方式变化；2)这种变化损害内皮屏障功能。作为实验细胞生物学的一项研究，这项工作标志着哈丁博士在理论物理方面的研究生工作有所不同。因此，被指导的K25将提供必要的支持，以进行持续的培训和研究。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调查员奠定基础。环境：杰弗里·弗雷德伯格教授将担任哈丁博士的主要导师。弗雷德伯格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，他还对更广泛的细胞力学实验研究做出了贡献。他在培训新的研究人员方面有着良好的记录，曾担任过41名过去和现在的博士后和博士后实习生的主要导师。在完成培训的人中，9人成为独立首席调查人员，7人获得终身教职，6人是正教授。他也是最近更新的跨学科肺科学T32培训拨款和2个新的RO1拨款的PI。他的实验室的跨学科工作已经被广泛关注[2-5]。哈丁博士还将与弗雷德伯格教授保持密切联系的其他著名生理学家和临床医生密切合作，其中包括詹姆斯·P·巴特勒博士和阿图尔·马尔霍特拉博士。哈佛公共卫生学院毗邻马萨诸塞州总医院、布里格姆妇女医院和哈佛医学院，提供了良好的智力环境。哈丁博士还将与马萨诸塞州总医院的工作人员进行预约，在那里他将与泰勒·汤普森博士等ARDS专家密切合作。研究：ARDS是导致死亡的主要原因[6]。ARDS病理中最早的事件之一是内皮屏障的破裂[7]，这主要是由于内皮细胞之间形成间隙[8]。现在人们对信号转导和生物介体的了解很多，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来发现细胞令人惊讶的物理特性，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(光磁扭转细胞仪OMTC[11-15]和细胞映射流变仪[12，16])，我们现在能够全面表征肺内皮细胞单层的机制及其在疾病模型中的变化。

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.