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.

这项教师早期职业发展（职业）奖的目的是揭示物理力量如何使气道平滑肌和周围的组织能够共同工作以检测吸入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中。 这些会导致我们的气道收缩，使我们难以呼吸。尽管众所周知，气道由于气道平滑肌产生的力而受到收缩，但肌肉如何检测吸入的刺激物并产生按比例的力来了解。这项工作中获得的基本科学知识可能会导致新的疗法。 例如，针对气道细胞外部成分的疗法可能会给全球数百万在呼吸困难而挣扎的人中持续缓解。与实验室研究同时，该奖项将吸引学生并激发他们对周围世界的好奇心。具体来说，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，获得指导支持以及获得大学入学指导。在线教育模块将在偏远，农村地区的K-12教育者访问科学和工程学方面进行创新。这项工作将共同激发新一代的生物工程师，他们被迫了解维持人类健康并通过科学技术创造更好世界的基本机制。该项目调查了在平滑肌中新发现的现象的基础的机制，在平滑肌中，细胞可以将收缩刺激作为集体感知。在集体激动剂传感中，平滑肌细胞相互通信，使用其力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感知收缩刺激及其产生的整体力。目前尚不清楚平滑肌的集体行为及其对气道狭窄的影响的基础的机制。这样做的研究目的是阐明调节集体激动剂传感的机制，并了解基本机械生物学相互作用在调节气道口径中的影响。具体而言，这将检验一个假设，即通过多细胞平滑肌细胞合奏进行集体激动剂传感取决于其以力依赖性方式动态改变单个细胞之间的连通性的能力。为此，我们设定了以下目标：1）测试以下假设：平滑肌细胞之间的机械信号传导调节SMC集合中的动力学感应。 2）量化深呼吸的影响对平滑肌细胞集合的力反应的影响。 3）确定机械生物学在调节肺组织中气道变窄中的作用。成功完成后，我们将为社区提供对迄今未知控制系统的详细描述，该系统对气道机芯进行了调节。该奖项反映了NSF的法定任务，并被认为是值得通过基金会的知识分子和更广泛影响的评估评估标准的评估值得支持的。