CAREER:Functional Heterogeneity in Cell Chemotaxis

这项提案的总体目标是制定一项以细胞迁移为重点的综合研究和教育计划。该奖项由国家科学基金会CBET部门支持，将使新工具的开发能够揭示内皮细胞趋化的机制。研究和教育将通过共同关注细胞-细胞外基质相互作用而整合。这项建议的研究目标是使用一种受定向进化启发的方法来研究趋化作用。将利用种群中自然的细胞到细胞的变异和异质性来揭示驱动内皮细胞对血管内皮生长因子(VEGF)反应的有效趋化的基本机制。将开发一种新的趋化装置，根据内皮细胞对血管内皮生长因子趋化梯度的反应的稳健性对其进行分类。将对这些亚群进行分析，以寻找导致不同趋化行为的潜在分子差异。实验将在2D和3D微环境中进行并进行比较。这项工作有可能揭示内皮细胞趋化的分子调控。此外，它在组织工程领域和癌症研究中具有明显的意义，在组织工程领域，受控的、定向的内皮细胞迁移可以使组织工程支架中的血管网络工程成为可能，在癌症研究中，对血管生成的更好理解可以使开发更有针对性的治疗方法来防止内皮细胞趋化反应。这一职业计划的更广泛影响是发展了一个跨学科的学习环境，将生物学和工程学在多个长度尺度(分子、细胞和组织水平)连接起来。将采用创新的教学方法和外联活动，向当地服务不足的农村社区的初中和高中女孩介绍生物和工程学的概念，并促进终身学习科学。

The overall goal of this proposal is to develop an integrated research and educational plan focused on cellular migration. This award, supported by the CBET division of the National Science Foundation, will enable the development of novel tools to uncover the mechanisms governing endothelial cell chemotaxis. Research and education will be integrated through their common focus on cell-extracellular matrix interactions. The research goal of this proposal is to use an approach inspired by directed evolution to study chemotaxis. The natural cell-to-cell variations and heterogeneities within a population will be exploited to uncover basic mechanisms that drive efficient chemotaxis in endothelial cells in response to vascular endothelial growth factor (VEGF). A novel chemotactic device will be developed which sorts endothelial cells based on the robustness of their response to chemotactic gradients of VEGF. These sub-populations will be analyzed for underlying molecular differences that are contributing to the differential chemotactic behaviors. Experiments will be performed in both 2D and 3D microenvironments and compared. This work has the potential to uncover critical insights into the molecular regulation of endothelial cell chemotaxis. Moreover, it has clear implications in the field of tissue engineering, where controlled, directed endothelial cell migration could enable the engineering of vascular networks in tissue engineered scaffolds, and in cancer research, where a better understanding of angiogenesis could enable the development of more targeted therapeutics to prevent endothelial cell chemotactic response. The broader impact of this CAREER program is the development of an interdisciplinary learning environment that connects biology and engineering across multiple length scales (molecular, cellular and tissue level). Innovative teaching methodologies and outreach activities will be employed to introduce middle and high school girls in the local, underserved, rural community to concepts in biology and engineering in a tractable way and to promote lifelong learning in science.