Laterally Mobile Ligands: Cellular Response to Dynamic Surfaces

描述（由申请人提供）：本研究的目的是设计横向移动的表面配体，不仅可以控制细胞行为，还可以让细胞主动重组与它们相互作用的表面。配体在生物材料表面的呈现对于细胞的粘附和功能是必不可少的。配体呈现的方式显著影响这些过程，从而推动了这项工作。第一个目标是创建一个配体-表面对，允许基于化学识别的受控的横向配体迁移。这将通过设计模块化配体来实现，这些配体在细菌中产生，包含细胞相互作用域和多个表面结合域。细胞相互作用域是一种已知的结合肽，与细胞表面的整合素受体结合。表面结合域是结合表面锚定蛋白的肽。多个表面结合域的独立表面附着和脱离将导致横向迁移或“行走”，而不会使整个配体与表面失去接触。第二个目的是确定配体结构对迁移率的影响。我们假设结构域的顺序和间距、表面结合结构域的数量和亲和力以及肽显示支架等特征将决定配体的流动性。第三个目标是利用这个系统来研究细胞在表面的行为和细胞操纵移动配体的能力。表征传统细胞对生物表面、粘附、扩散和运动的反应，将揭示由于移动配体对细胞行为的任何新的控制。然而，与传统表面不同，移动配体表面上的细胞将有机会主动组织或操纵表面配体。跟踪配体和相应的细胞表面受体将提供这种相互作用的证据。公共卫生相关性：这项工作与公共卫生的相关性在于制造用于治疗或组织工程应用的控制细胞行为的生物材料。显示横向移动配体的表面是一种新型的生物表面，它不仅支持细胞，而且促进细胞与表面之间独特的相互作用。

DESCRIPTION (provided by applicant): The objective of this research is to engineer laterally mobile surface ligands that not only confer control over cell behavior but also allow cells to actively reorganize the surface with which they are interacting. Presentation of ligands on biomaterial surfaces is essential for cell adhesion and function. The manner in which ligands are presented significantly affects these processes, thereby motivating this work. The first aim is to create a ligand-surface pair that allows controlled, lateral ligand migration based on chemical recognition. This will be achieved by designing modular ligands, produced in bacteria, that contain a cell interaction domain and multiple surface binding domains. The cell interaction domain is a known binding peptide to an integrin receptor on the cell surface. The surface binding domains are peptides that bind surface anchor proteins. Independent surface attachment and detachment of multiple surface binding domains will result in lateral migration, or "walking", without the entire ligand losing contact with the surface. The second aim is to determine the effect of ligand structure on mobility. We hypothesize that features such as domain order and spacing, number and affinity of surface binding domains, and peptide display scaffolds will dictate ligand mobility. The third aim is to use this system to study cell behavior on the surface and the ability of cells to manipulate mobile ligands. Characterization of traditional cell responses to biosurfaces, adhesion, spreading, and motility, will reveal any new control over cell behavior due to mobile ligands. However, unlike traditional surfaces, cells on the mobile ligand surface will have the opportunity to actively organize or manipulate surface ligands. Tracking the ligands and corresponding cell surface receptors will provide evidence of this type of interaction. PUBLIC HEALTH RELEVANCE: The relevance of this work to public health lies in fabrication of biomaterials that control cell behavior for therapeutic or tissue engineering applications. Surfaces displaying laterally mobile ligands are a new type of biosurface that not only support cells but also promote unique interactions between cells and surfaces.