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：在健康肺中拮抗支气管收缩的所有因素中，深呼吸是最有效的。然而，在哮喘肺中，这种保护现象基本上是在自发的哮喘发作中，有时甚至会逆转。有些人建议深呼吸无法扩张的哮喘性气道可能是事实的重要原因戒断气道变窄。为了解释这些观察结果，我们最近的发现呼吁关注呼吸实际上伸展了气道壁，即施加的圆周菌株的大小。反过来，周向应变必须随两个物理因素的函数而变化：（i）呼吸道壁中细胞和细胞外基质（ECM）的非收缩元件，以及（ii）产生的力通过气道平滑肌（ASM）本身。但是，几乎不可能直接测量这些因素及其在人体内气道环境中的相对贡献。在没有这样的知识，理事机制将保持较差的阐明，关键的病理生理见解将保持隐藏。例如，在哮喘中，确实增强了ECM刚度使气道耐火深层灵感的有益影响？还是疾病的病理生理学以异常的ASM为主易于疗程？为了找到这些问题的答案，在这项基础赠款中，我们建议开发新颖的实现测量技术。使用一种生物力学方法，我们开创了称为牵引力mi的率我们在AIM 1中提出crscopy（TFM），以测量ASM产生的收缩力，该收缩力与位于在完整的人体内气道中，并受到模拟呼吸。我们建议在AIM 2中脱颖而出维洛普新技术，以测量气道墙的细胞外基质（ECM）组件的原位刚度并将局部ECM刚度与局部细胞ECM寄生应力相关联。

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.

DOI：
10.1242/jcs.196881
发表时间：
2017-03-01
期刊：
Journal of cell science
影响因子：
4
作者：
Jiu Y;Peränen J;Schaible N;Cheng F;Eriksson JE;Krishnan R;Lappalainen P
通讯作者：
Lappalainen P

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

DOI：
10.1016/j.bbrc.2021.11.030
发表时间：
2022-01-01
期刊：
Biochemical and biophysical research communications
影响因子：
3.1
作者：
Husain A;Khadka A;Ehrlicher A;Saint-Geniez M;Krishnan R
通讯作者：
Krishnan R

Traction Force Screening Enabled by Compliant PDMS Elastomers.

由合规 PDMS 弹性体实现牵引力筛选。

DOI：
10.1016/j.bpj.2018.02.045
发表时间：
2018
期刊：
Biophysical journal
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,JohnK;Saint-Geniez,Magali;Krishnan,Ramaswamy;Ehrlicher,AllenJ
通讯作者：
Ehrlicher,AllenJ