CAREER: Biomechanics of Leader Cells

该奖项全部或部分由《2021年美国救援计划法案》（公法117-2）资助。该学院早期职业发展（Career）奖将支持研究研究细胞群的迁移，特别是来自外部环境的机械力和细胞机械力如何引导迁移。细胞群的迁移是许多组织发育所必需的。然而，移徙也可能是发育异常或疾病进展的标志。为了使细胞一起移动，一个独特的细胞子集，即那些被称为先导细胞的细胞，必须移动到前面。领头细胞接收来自周围环境的信号，并将信号发送给群体中的其他细胞，这样它们就可以一起移动。然而，领导细胞是如何独特地执行这些功能的，在很大程度上仍然是未知的。这项研究将开始揭示领导细胞如何感知、解释和发送机械信号。这将提供对细胞群如何一起运动的更全面的理解。这项研究将辅以一项教育计划，以招募和留住STEM领域的不同学生群体。未被充分代表的少数民族、女性和第一代学生将通过研究、指导和为高中生、本科生和研究生开发课程的方式参与进来。工作也将与弗吉尼亚州的K-12教师一起进行，使用探究式科学课程。这些活动将通过基于研究成果的动手实验来提高K-12学生对STEM的认识。本研究的具体目标是了解领导细胞、生物力学细胞外基质（ECM）线索和细胞力学如何交织在一起，影响细胞群在集体迁移过程中的迁移。中心假设是，先导细胞通过偏向生物力学线索、间质流体流动和维持定向集体迁移所需的细胞生成力的方向增加的突出粘附而极化到前沿。利用一种新颖的体外3D微生理系统，该系统可以复制动态ECM信号，并结合细胞团来模拟和诱导集体迁移，本研究将探讨：1)领导细胞如何从集体单位内部向间质流体流动方向极化，2)领导细胞是否机械连接，以及领导细胞之间的机械力如何启动和维持集体迁移。了解领导细胞如何发挥作用并导致集体迁移不仅将扩大我们对集体迁移驱动的发育过程的理解，而且还将为解决领导细胞驱动的集体迁移出错的发育异常或疾病进展的治疗设计提供新的视角。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识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 award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2).This Faculty Early Career Development (CAREER) award will support research to investigate the migration of groups of cells, specifically, how mechanical forces from the external environment and cellular mechanical forces guide migration. The migration of groups of cells is necessary for development of many tissues. However, migration can also be a sign of development abnormalities or disease advancement. For cells to move together, a unique sub-set of cells, those called the leader cells, must move to the front. The leader cells receive signals from their surroundings and send signals to other cells in the group so they can all move together. However, how leader cells are uniquely able to carry out these functions is still largely unknown. This research will begin to unravel how leader cells sense, interpret, and send mechanical signals. This will provide a more comprehensive understanding of how groups of cells move together. This research will be complemented by an educational program to recruit and retain diverse populations of students in STEM. Underrepresented minorities, women, and first-generation students will be engaged through research, mentoring, and course development for high school, undergraduate and graduate students. Work will also be conducted with K-12 teachers in Virginia using inquiry-based science lessons. The activities will promote STEM awareness to K-12 students using hands-on experiments based on research findings. The specific goal of this research is to understand how leader cells, biomechanical extracellular matrix (ECM) cues, and cellular mechanics are intertwined to influence the migration of clusters of cells in a process known as collective migration. The central hypothesis is that leader cells polarize to the leading edge through increased protrusive adhesions biased in the direction of the biomechanical cue, interstitial fluid flow, and cellular generated forces required to sustain directed collective migration. Using a novel, in vitro, 3D microphysiological system that can replicate dynamic ECM cues and incorporate cell clusters to model and induce collective migration, this research will investigate: 1) how leader cells polarize from within a collective unit to the front in the direction of interstitial fluid flow, and 2) if leader cells are mechanically connected and how mechanical forces between leader cells initiate and sustain collective migration. Understanding how leader cells function and lead to collective migration will not only expand our understanding of collective migration driven developmental processes, but also provide a new perspective for therapy design addressing development abnormalities or disease progression where leader cell driven collective migration has gone awry.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.