NSF Postdoctoral Fellowship in Biology FY 2022: The Mechanical Engineering of Dendritic Cell Migration

这项研究将探索影响细胞运动(称为细胞迁移)的生物物理机制和遗传学。这位研究员将使用树突状细胞作为这项工作的模型。树突状细胞是一种免疫细胞，当它们巡逻寻找外来病原体(即细菌)时，它们会在组织中迁移。然而，人们对免疫细胞如何在组织中挤压和迁移知之甚少，这些组织的空间往往比细胞本身小几百到几千倍。这位研究员将(1)确定树突状细胞如何推动、拉动和挤压组织，(2)研究组织的机械特性如何影响树突状细胞的迁移，以及(3)发现促进或抑制细胞迁移的基因。这些研究将揭示免疫细胞迁移的基本见解，并可能揭示细胞迁移的新机制。被确认参与树突状细胞迁移的基因可能会潜在地指导新的免疫疗法。此外，该研究员还旨在通过将机械工程的观点和工具引入生物物理学和免疫学领域，并指导学术领域中代表性不足的学生，来增加多样性和包容性。组织及其细胞外基质可以表现出粘弹性，在机械力的作用下发生不可逆转的变形。在粘弹性基质中，细胞可以产生能够诱导基质流动的力，并以塑料的方式创造和扩展开口。这项研究假设，首先，树突状细胞利用其细胞核产生贴壁细胞中没有的异常力，可塑性地开辟了一条促进迁移的途径；其次，基质的力学属性，如可塑性、刚性和粘附性，影响了迁移行为。使用可调生物材料进行3D培养和共聚焦显微镜，该研究员将研究细胞迁移以及不同的基质属性如何影响迁移。此外，考虑到树突状细胞与典型的贴壁细胞如上皮细胞、成纤维细胞和癌细胞相比，其三维迁移表现出明显的不同，该研究人员假设可能存在与细胞迁移有关的未知的关键基因。这项研究的目的是利用全基因组CRISPR筛选和基于微流控技术的单细胞凝胶封装方法进行迁移分析，以发现这些基因。在进行研究的同时，该研究员将受益于机械生物学和免疫学方面的培训。该项目还将通过由主办机构支持的外展项目为本科生和研究生提供指导，从而帮助招募和留住历史上代表性不足的个人。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。

This research will explore the biophysical mechanisms and genetics that influence the movement of cells (called cell migration). The fellow will use dendritic cells as a model for this work. Dendritic cells are immune cells that migrate through tissues as they patrol for foreign pathogens (i.e., bacteria). However, it is poorly understood how the immune cells can squeeze and migrate through tissues which often have spaces hundred to thousand times smaller than the cells themselves. The Fellow will (1) determine how dendritic cells push, pull, and squeeze their way through tissues, (2) investigate how mechanical properties of the tissues impact dendritic cell migration, and (3) discover genes that either promote or suppress the cell migration. These studies will reveal fundamental insights into the immune cell migration and potentially uncover new mechanisms of cell migration. The genes identified as being involved in dendritic cell migration could potentially guide novel immunotherapies. In addition, the Fellow also aims to increase diversity and inclusion by bringing perspectives and tools of mechanical engineering into the fields of biophysics and immunology and mentoring underrepresented students in the academic fields. Tissues and their extracellular matrices can exhibit viscoelasticity, undergoing irreversible deformations in response to mechanical forces. In viscoelastic matrices, cells can generate forces which can induce the matrix to flow and create and expand an opening in a plastic fashion. The research hypothesizes that first, dendritic cells use its nucleus to create exceptional forces that are not found in adherent cells, plastically opening a path to facilitate migration; second, the matrix mechanical properties such as plasticity, stiffness, and adhesivity impact the migration behaviors. Using tunable biomaterials for 3D culture and confocal microscopy, the Fellow will study the cell migration and how varying matrix properties impact the migration. Moreover, considering that dendritic cells exhibit striking differences in their 3D migration compared to typical adherent cells such as epithelial cells, fibroblasts, and cancer cells, the Fellow assumes that there may be critical genes involved in the cell migration that are unknown. The research aims to discover the genes using genome-wide CRISPR screen and microfluidics-based approach for single cell-in-gel encapsulation for a migration assay. The Fellow will benefit from training in mechanobiology and immunology while conducting the studies. This project will also aid in recruitment and retention of historically underrepresented individuals by providing mentorship to undergraduate and graduate students through outreach programs supported by the host institution.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.