CAREER: Biomechanics of Leader Cells

该奖项全部或部分根据2021年美国救援计划法案（公法117-2）资助。该教师早期职业发展（CAREER）奖将支持研究调查细胞群的迁移，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，迁移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，即所谓的领导细胞，必须移动到前面。领导细胞接收来自周围环境的信号，并向组中的其他细胞发送信号，以便它们可以一起移动。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。这将提供一个更全面的了解细胞群如何一起移动。这项研究将得到一项教育计划的补充，以招募和留住STEM领域的多元化学生。代表性不足的少数民族，妇女和第一代学生将通过研究，指导和高中，本科和研究生课程开发参与。工作也将进行与K-12教师在弗吉尼亚州使用探究为基础的科学课程。这些活动将通过基于研究结果的实践实验，向K-12学生宣传STEM意识。这项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，以影响细胞簇在称为集体迁移的过程中的迁移。核心假设是，前导细胞通过增加的粘附偏向于生物力学线索的方向，间质液流动，细胞产生的力量，以维持定向集体迁移。使用一种新型的体外3D微生理学系统，该系统可以复制动态ECM线索并结合细胞簇来建模和诱导集体迁移，本研究将研究：1）引导细胞如何从集合单元内沿组织液流动方向向前移动，以及2）前导细胞是否机械连接以及前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，不仅会扩大我们对集体迁移驱动的发育过程的理解，而且还为治疗设计提供了一个新的视角，解决了领导细胞驱动的集体迁移出现问题的发育异常或疾病进展。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会知识分子的评估来支持。优点和更广泛的影响审查标准。

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.