Engineering composite materials to promote cell motility

描述（由申请人提供）：细胞迁移在正常生物学过程中起关键作用，如发育模式、伤口愈合和免疫反应。与此同时，使异常细胞迁移的突变支撑了癌症转移等病理的发展。此外，操纵细胞迁移是涉及生物材料植入物定殖的医疗技术中的关键设计考虑。天然细胞外基质蛋白的模块化结构激发了呈现协同促进细胞迁移的多个表位的合成生物材料的设计。虽然表位如含RGD的纤连蛋白（FN）的中央细胞结合结构域（CCBD）有效地介导细胞粘附，但FN内的互补结构域如肝素结合结构域（HBD）显著增强CCBD介导的细胞铺展、膜延伸活性、粘着斑（FA）形成和粘着斑激酶（FAK）磷酸化。由于这些生物物理和生物化学事件是细胞迁移的组成部分，我们假设操纵生物材料上CCBD和HBD的表面密度可能是调节细胞迁移速度的有效方法。重要的是，由于细胞迁移涉及这些中间过程的复杂协调，目前还不清楚是否伴随的扩展，膜延伸活动，FA形成和生化信号的增强单调相关的细胞迁移增强。因此，拟议工作的总体目标是阐明CCBD和HBD在促进细胞迁移方面的定量协同作用，如以下具体目标所概述的：（1）设计一种新的基质，用于以充分表征的、可调节的绝对和相对量共同呈递CCBD和HBD，以及（2）量化细胞迁移速度对CCBD和HBD的依赖性。从拟议的工作的结果将提供设计CCBD/HBD复合材料，促进细胞迁移的医疗技术中的应用，涉及生物材料的殖民策略。

DESCRIPTION (provided by applicant): Cell migration plays a key role in normal biological processes such as developmental patterning, wound healing and immune response. Meanwhile, mutations that enable aberrant cell migration underpin the development of pathologies such as cancer metastasis. In addition, manipulating cell migration is a key design consideration in medical technologies that involve colonization of biomaterial implants. The modular construction of natural extracellular matrix proteins motivates the design of synthetic biomaterials presenting multiple epitopes that synergistically promote cell migration. While epitopes such as the RGD-containing, central cell-binding domain (CCBD) of fibronectin (FN) effectively mediate cell adhesion, complementing domains within FN such as the heparin-binding domain (HBD) significantly enhance CCBD-mediated cell spreading, membrane extension activity, focal adhesion (FA) formation and focal adhesion kinase (FAK) phosphorylation. Since these biophysical and biochemical events are integral elements of cell migration, we hypothesize that manipulating the surface density of CCBD and HBD on a biomaterial may be an effective method to tune cell migration speed. Importantly, because cell migration involves complex coordination of these intermediate processes, it is unclear whether concomitant enhancements in spreading, membrane extension activity, FA formation and biochemical signaling correlate monotonically to enhanced cell migration. Thus, the overall objective of the proposed work is to elucidate the quantitative synergy between CCBD and HBD in promoting cell migration, as outlined by the following Specific Aims: (1) to engineer a novel substratum for co-presenting CCBD and HBD in well-characterized, adjustable absolute and relative amounts, and (2) to quantify the dependence of cell migration speed on CCBD and HBD. Results from the proposed work will offer strategies for designing CCBD/HBD composite materials that promote cell migration for application in medical technologies involving colonization of biomaterials.