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

职业：阐明集体细胞-基质相互作用在气道狭窄的力学生物学中的作用

• 批准号: 2047207
• 负责人: Harikrishnan Parameswaran
• 金额: $ 60.27万
• 依托单位: Northeastern University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2047207&HistoricalAwards=false
• 关键词: CAREER; Elucidating; Role; Collective; Cell

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.

该学院早期职业发展奖旨在揭示物理力量如何使呼吸道平滑肌肉和周围组织协同工作，以检测吸入的刺激物并调节呼吸道收缩。日常生活使我们暴露在许多可吸入的刺激物中。这些会导致我们的呼吸道收缩，使我们呼吸困难。虽然众所周知，呼吸道收缩是由于呼吸道平滑肌产生的力，但肌肉如何检测吸入的刺激物并产生比例的力还不是很清楚。在这项工作中获得的基本科学知识可以带来新的治疗方法。例如，针对呼吸道细胞外成分的疗法可能会为全球数百万与呼吸困难作斗争的人提供持久的缓解。在实验室研究的同时，这个奖项将吸引学生并激发他们对周围世界的好奇心。具体地说，来自少数族裔群体的高中生将有机会进行实验室研究，接受指导支持，并为大学入学提供指导。在线教育模块将使偏远农村地区的K-12教育工作者能够接触到科学和工程教学方面的创新。这项工作将共同激励新一代生物工程师，他们有动力了解维持人类健康并通过科学技术创造更美好世界的基本机制。这个项目研究了在平滑肌中新发现的一种现象的机制，在这种现象中，细胞可以共同工作，作为一个集体来感觉收缩刺激。在集体激动剂感应中，平滑肌细胞相互通信，利用它们的力量来调节细胞间钙波的频率。通过相互交流，这个整体可以完全改变每个细胞对收缩刺激及其产生的总力的感知方式。目前尚不清楚平滑肌这种集体行为的机制及其对气道狭窄的影响。这项研究的目的是阐明调节集体激动剂感觉的机制，并了解潜在的机械生物学相互作用在调节气道口径中的影响。具体地说，这将检验一种假设，即多细胞平滑肌细胞系对集体激动剂的感知依赖于其以力依赖的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)检验平滑肌细胞之间的机械信号调节SMC整体激动剂感觉的假设。2)量化深呼吸对平滑肌细胞群作用力反应的影响。3)明确机械生物学在调节肺组织内气道狭窄中的作用。在成功完成后，我们将向社区提供一个迄今为止未知的控制系统的详细描述，该系统管理呼吸道口径。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。