CAREER: LungEx for Probing Multiscale Mechanobiology of Pulmonary Respiration-Circulation Coupling in Real-Time

该学院早期职业发展（CAREER）资助将为实时和多尺度肺机械生物学提供前所未有的见解，该机械生物学将单气囊与肺的整个器官功能联系起来。这将通过利用一种新型的透明胸腔来实现，该胸腔提供了以高空间和时间分辨率探测肺机械生物学的变革能力。计划中的研究将在细胞水平和实时提供对肺功能的基础了解，包括呼吸，循环和免疫。以前所未有的时空分辨率了解肺功能（和功能障碍）将解决肺机械生物学和机械免疫学新兴领域的关键挑战。对实验和数学的多学科和多尺度方法的关注，也将为各级学生提供令人兴奋的机会，让他们参与肺生物力学和机械生物学的未探索领域。该研究和教育计划的中心目标是激励和培训从K-12到研究生院的学生，从概念上思考定量和跨学科方法如何帮助理解肺微生理学。这项工作将利用一种新的平台，称为LungEx，其中包括在接近体内生理条件下的小鼠肺的离体维持。LungEx的一个关键和新颖的元素是一个透明的胸腔，称为“晶体”胸腔，具有完整的天然胸腔的几何和物理特性。使用水晶胸腔将允许，第一次，可视化的动态肺微生理学实时，在细胞的分辨率，并在几乎整个表面的肺。利用变革性的LungEx技术，该项目的目标将通过以下方式实现：1）探索肺泡扩张如何与毛细血管水平的红细胞运输和氧气运输相关联，2）确定肺泡扩张是否是内脏扩张中流动的主要驱动力，以及3）在单细胞水平上探索免疫细胞与毛细血管的实时动态机械相互作用。通过将这项研究与精心设计的各级学生教育计划相结合，我们将培养下一代肺生物力学和机械生物学的劳动力，以在基础肺生物学和生理学方面做出发现。该奖项反映了NSF的法定使命，并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，被认为值得支持。

This Faculty Early Career Development (CAREER) grant will provide unprecedented insight into the real-time and multiscale lung mechanobiology that bridges single-air sac to whole-organ functions of the lung. This will be achieved by utilizing a novel transparent ribcage that provides transformative capabilities to probe lung mechanobiology at high spatial and temporal resolutions. The planned research will provide foundational understanding of lung function including respiration, circulation, and immunity, at the cellular level and in real-time. Understanding the lung function (and dysfunction) at an unprecedented spatiotemporal resolution will address key challenges in the emerging fields of lung mechanobiology and mechano-immunity. The focus on multidisciplinary and multiscale approaches, both experimental and mathematical, will also provide exciting opportunities for students on all levels to participate in the unexplored area of pulmonary biomechanics and mechanobiology. The central goal of this research and educational program is to inspire and train students from K-12 to graduate school to think conceptually about how quantitative and interdisciplinary approaches can help understand lung microphysiology. This work will utilize a novel platform, termed LungEx, that includes the ex vivo maintenance of the mouse lung in near in vivo physiological conditions. A key and novel element of LungEx is a transparent ribcage, termed “crystal” ribcage, with geometrical and physical properties of the intact native ribcage. Use of the crystal ribcage will allow, for the first time, visualization of the dynamics of lung microphysiology in real-time, at the cellular resolution, and over nearly the entire surface of the lung. Utilizing the transformative LungEx technology, the project goals will be achieved by 1) probing how alveolar distension is coupled to red blood cell trafficking and oxygen transport at the capillary level, 2) determining whether alveolar lymphatics serves as the main driver of flow in visceral lymphatics, and 3) probing the real-time dynamic mechanical interactions of immune cells with capillaries at the single cell level. By integrating this research with a carefully designed educational plan for students at all levels, we will train the next generation workforce in pulmonary biomechanics and mechanobiology to make discoveries in foundational pulmonary biology and physiology.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.