Monitoring contractile forces during airway constriction

监测气道收缩期间的收缩力

基本信息

批准号：
9318550
负责人：
RAMASWAMY KRISHNAN
金额：
$ 27.62万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9318550
关键词：
Abate Acute Animals Asthma Atomic Force Microscopy Attention Attenuated Benchmarking Biological Models Biology Biomechanics Breathing Bronchoconstriction Cells Conflict (Psychology)Cultured Cells Disease Elasticity Elements Extracellular Matrix Fiber Fibrinogen Fluorescence Recovery After Photobleaching Foundations Functional disorder Goals Grant Human In Situ In Vitro Injectable Investigation Knowledge Lung Maps Measurement Measures Mechanical Stress Mechanics Methods Monitor Muscle Muscle Cells Muscle Contraction Physiology Refractory Research Resolution Slice Stress Stretching System Techniques Technology Tenuate Thinness Time Tissues Traction asthmatic asthmatic airway base constriction design follow-up improved in vivo innovation insight new technology novel pre-clinical quantitative imaging respiratory smooth muscle response spatiotemporal temporal measurement theories

项目摘要

Project summary: Among all factors known to antagonize bronchoconstriction in a healthy lung, a deep breath is among the most effective. In the asthmatic lung, however, this protective phenomenon is substantially at- tenuated and during a spontaneous asthmatic attack it is sometimes even reversed. Some have suggested that the inability of a deep breath to dilate the constricted asthmatic airway might be an important cause of ex- cessive airway narrowing. To explain these observations, our recent findings call attention to the extent to which breathing actually stretched the airway wall, i.e. the magnitude of circumferential strain that is imposed. The circumferential strain, in turn, must vary inversely as a function of two physical factors: (i) stiffness of the non-contractile elements of the cells and extracellular matrix (ECM) in the airway wall, and, (ii) force generated by the airway smooth muscle (ASM) itself. However, it has been nearly impossible to directly measure these factors and their relative contributions in the settings of the intraparenchymal human airway. In the absence of such knowledge, governing mechanisms will remain poorly elucidated and key pathophysiological insights will remain hidden. For example, in asthma, does enhanced ECM stiffness render the airway refractory to the beneficial effects of deep inspirations? Or is the disease pathophysiology dominated by aberrant ASM con- tractility? To find answers to these questions, in this foundational grant, we propose to develop novel enabling measurement technologies. Using a biomechanical approach that we have pioneered called traction force mi- croscopy (TFM), we propose in aim 1 to measure contractile forces generated by the ASM that is situated with- in intact human intraparenchymal airways and subjected to simulated breathing. We propose in aim 2 to de- velop new technology to measure in situ stiffness of extracellular matrix (ECM) components of the airway wall and to correlate local ECM stiffness with local cell-ECM borne stresses.

项目摘要：在所有已知的对抗健康肺部支气管收缩的因素中，深呼吸是最有效的之一。然而，在哮喘肺中，这种保护现象基本上是- 减弱，在自发性哮喘发作期间，有时甚至会逆转。有些人建议深呼吸无法扩张狭窄的哮喘气道可能是哮喘发作的一个重要原因气道持续变窄。为了解释这些观察结果，我们最近的发现引起人们对以下问题的关注：哪种呼吸实际上拉伸了气道壁，即施加的周向应变的大小。反过来，周向应变必须作为两个物理因素的函数成反比变化：(i) 材料的刚度气道壁中细胞和细胞外基质 (ECM) 的非收缩成分，以及 (ii) 产生的力气道平滑肌 (ASM) 本身。然而，直接测量这些几乎是不可能的。因素及其在人实质内气道环境中的相对贡献。在没有这些知识、控制机制仍不清楚，关键的病理生理学见解将保持隐藏。例如，在哮喘中，增强的 ECM 硬度是否会使气道难以耐受深刻灵感的有益影响？或者疾病的病理生理学是由异常的 ASM con- 主导的？牵引力？为了找到这些问题的答案，在这笔基础拨款中，我们建议开发新颖的使能技术测量技术。使用我们首创的称为牵引力 mi- 的生物力学方法透视（TFM），我们在目标 1 中建议测量 ASM 产生的收缩力，该收缩力位于 - 在完整的人实质气道中并进行模拟呼吸。我们在目标 2 中建议去开发新技术来测量气道壁细胞外基质 (ECM) 成分的原位硬度并将局部 ECM 刚度与局部细胞 ECM 承受的应力相关联。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Vimentin intermediate filaments control actin stress fiber assembly through GEF-H1 and RhoA.

波形蛋白中间丝通过 GEF-H1 和 RhoA 控制肌动蛋白应力纤维组装。

DOI：
发表时间：
2017-03-01
期刊：
影响因子：
4
作者：
Jiu, Yaming;Peränen, Johan;Schaible, Niccole;Cheng, Fang;Eriksson, John E;Krishnan, Ramaswamy;Lappalainen, Pekka
通讯作者：
Lappalainen, Pekka

Substrate stiffening promotes VEGF-A functions via the PI3K/Akt/mTOR pathway.

基质硬化通过 PI3K/Akt/mTOR 途径促进 VEGF-A 功能。

DOI：
发表时间：
2022-01-01
期刊：
影响因子：
3.1
作者：
Husain, Amjad;Khadka, Arogya;Ehrlicher, Allen;Saint;Krishnan, Ramaswamy
通讯作者：
Krishnan, Ramaswamy

Traction Force Screening Enabled by Compliant PDMS Elastomers.

由合规 PDMS 弹性体实现牵引力筛选。

DOI：
发表时间：
2018
期刊：
影响因子：
3.4
作者：
Yoshie, Haruka;Koushki, Newsha;Kaviani, Rosa;Tabatabaei, Mohammad;Rajendran, Kavitha;Dang, Quynh;Husain, Amjad;Yao, Sean;Li, Chuck;Sullivan, John K;Saint;Krishnan, Ramaswamy;Ehrlicher, Allen J
通讯作者：
Ehrlicher, Allen J