CAREER: Elucidating the Role of Collective Cell-Matrix Interactions in the Mechanobiology of Airway Narrowing

该学院早期职业发展（CAREER）奖旨在揭示物理力量如何使气道平滑肌和周围组织共同工作，以检测吸入的刺激物并调节气道的收缩。日常生活使我们暴露于许多吸入的刺激物。 这些会导致我们的气道收缩，使我们呼吸困难。虽然已知气道收缩是由于气道平滑肌产生的力，但肌肉如何检测吸入的刺激物并产生成比例的力还没有很好地理解。在这项工作中获得的基本科学知识可以导致新的疗法。 例如，靶向气道细胞外成分的疗法可以为全球数百万呼吸困难患者提供持久的缓解。在实验室研究的同时，该奖项将吸引学生并激发他们对周围世界的好奇心。具体而言，来自代表性不足的少数群体的高中生将有机会进行实验室研究，接受指导支持和大学入学辅导。在线教育模块将为偏远农村地区的K-12教育工作者提供科学和工程教学创新。这项工作将激励新一代生物工程师，他们将致力于了解维持人类健康的基本机制，并通过科学技术创造一个更美好的世界。本项目研究了平滑肌中一种新发现的现象的机制，在这种现象中，细胞可以共同工作，以集体的方式感知收缩刺激。在集体激动剂感知中，平滑肌细胞相互交流，利用它们的力量来调节细胞间钙波的频率。通过相互交流，整体可以完全改变每个细胞如何感知收缩刺激及其产生的整体力量。平滑肌的这种集体行为的机制及其对气道狭窄的影响目前尚不清楚。本研究的目的是阐明调节集体激动剂感知的机制，并了解调节气道口径的潜在机械生物学相互作用的影响。具体地说，这将测试一个假设，即多细胞平滑肌细胞集合的集体激动剂感知依赖于其以力依赖性方式动态改变单个细胞之间的连接的能力。为此，我们建立了以下目标：1）验证平滑肌细胞之间的机械信号调节SMC集合体中激动剂感受的假设。2)量化深呼吸对平滑肌细胞集合的力响应的影响。3)确立机械生物学在调节肺组织气道狭窄中的作用。成功完成后，我们将向社会提供一个迄今为止未知的控制系统，调节气道口径的详细说明。这个奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

This Faculty Early Career Development (CAREER) award aims to reveal how physical forces enable the airway smooth muscle and the surrounding tissue to work together to detect inhaled irritants and regulate the constriction of airways. Everyday life exposes us to many inhaled irritants. These can cause our airways to constrict, making it difficult for us to breathe. Although it is known that airways constrict due to the force generated by the airway smooth muscle, how the muscle detects the inhaled irritant and generates a proportionate force is not well understood. The basic scientific knowledge gained in this work can lead to new therapies. For example, therapies that target the airway's extracellular components may offer lasting relief for the millions of people worldwide who struggle with breathing difficulties. In parallel with the laboratory research, this award will engage students and pique their curiosity about the world around them. Specifically, high school students from underrepresented minority groups will have opportunities to perform laboratory research, receive mentoring support, and coaching for college admission. Online educational modules will make innovations in teaching science and engineering accessible for K-12 educators in remote, rural areas. Together, this work will inspire a new generation of bioengineers who are driven to understand the fundamental mechanisms that maintain human health and create a better world through science and technology. This project investigates the mechanisms that underlie a newly discovered phenomenon in the smooth muscle where cells can work together to sense contractile stimuli as a collective. In collective agonist sensing, smooth muscle cells communicate with each other, using their force to modulate the frequency of intercellular calcium waves. By communicating with each other, the ensemble can completely change how each cell perceives contractile stimulus and the overall force it generates. The mechanisms that underlie this collective behavior of the smooth muscle and its implications for airway narrowing are currently unknown. The research goal of this is to elucidate the mechanisms that regulate collective agonist sensing and to understand the impact of the underlying mechanobiological interactions in regulating airway caliber. Specifically, this will test a hypothesis that collective agonist sensing by a multicellular smooth muscle cell ensemble relies on its ability to dynamically change the connectivity among individual cells in a force-dependent manner. To this end, we have set up the following aims: 1) Test the hypothesis that mechanical signaling between smooth muscle cells regulates agonist sensing in SMC ensembles. 2) Quantify the impact of deep breaths on the force response of smooth muscle cell ensembles. 3) Establish the role of mechanobiology in regulating airway narrowing in lung tissue. Upon successful completion, we will provide the community with a detailed description of a hitherto unknown control system that regulates airway caliber.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.