REU: Engineered Platforms for Control of Multi-cue Migration

REU：用于控制多线索迁移的工程平台

• 批准号: 10809473
• 负责人: Ian Christopher Schneider
• 金额: $ 1.31万
• 依托单位: IOWA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10809473
• 关键词: 3-Dimensional; Actinin; Adhesions; Alginates; Biological; Bundling; Cells; Cicatrix; Collagen; Collagen Fiber; Collagen Fibril; Complex; Coupled; Cues; Cytoskeleton; Decision Making; Dermal; Development; Disease; Drug Targeting; Engineering; Environment; Extracellular Matrix; F-Actin; Fiber; Fibroblasts; Gel; Goals; Growth; Immune; Immune response; In Vitro; Individual; Invaded; Lead; Malignant Neoplasms; Mechanics; Mediating; Microtubules; Molecular; Myosin Type II; Neoplasm Metastasis; Normal Cell; Pathologic; Pathologic Processes; Pathway interactions; Physiological; Physiological Processes; Play; Process; Research; Role; Structure; Sum; System; Testing; Therapeutic; Tissue Engineering; Tissues; Work; cancer cell; cell motility; cell type; chronic wound; crosslink; design; directional cell; drug candidate; drug discovery; flexibility; imprint; in vivo; insight; mechanical properties; migration; next generation; predictive marker; preference; response; self assembly; spatial integration; synergism; transmission process; traumatic wound; tumor microenvironment; virtual; wound bed; wound dressing; wound healing

ABSTRACT The goal of this project is to use engineered extracellular matrix environments leveraging structural and me- chanical control over the extracellular matrix to examine the mechanisms by which cells respond to multiple directional migration cues. Cell migration plays an important role in many physiological and pathological pro- cesses such as wound healing, development and cancer invasion. Frequently migration is not simply random, but directed towards targets through recognition of aligned extracellular matrix fibers or gradients in stiffness, generating contact guidance and durotaxis, respectively. In many biological contexts these cues are presented simultaneously, forcing cells to integrate this information. For instance, gradients of stiffness and aligned colla- gen are generated within the wound bed to direct dermal fibroblast migration. Similar fiber structures and gra- dients stimulate cancer cell migration out of the tumor microenvironment and normal cells including stromal and immune cells towards the tumor microenvironment. While there is a firm understanding of how cells re- spond to individual directional cues, virtually nothing is known about how cells integrate multiple cues and make migrational decisions based on that integration. Furthermore, there is a hypothesis that contact guidance and durotaxis are overlapping directional cell migration mechanisms, but this has not been rigorously tested. Mechanistic understanding of multi-cue directional migration will require a refined understanding of how the F- actin and microtubule networks operates. Indeed, some evidence suggests that contact guidance and durotax- is may use slightly different F-actin network structures, since contact guidance is thought to be governed by F- actin fiber structures, but durotaxis is not. Engineering approaches will be taken to design in vitro environments that allow for independent tuning of contact guidance and durotaxis in both 2D and 3D environments. Further- more, the effect of F-actin branching, bundling and contraction in allowing cells to prefer aligned fibers of colla- gen or gradients of stiffness will be tested. This will uncover shared or competing molecular pathways involved when these two directional migration cues are present in isolation and together. Understanding how cells mi- grate in response to multiple cues has broad impact on several biomedical fields including tissue engineering and disease therapeutics. Determining how cells respond to multiple cues in vitro will allow us to predict cell responses in wound healing, development, cancer invasion and immune response leading to drug candidates as in cancer or strategies to enhance wound healing and immune response.

抽象的 该项目的目标是利用工程化的细胞外基质环境，利用结构和机制 对细胞外基质的机械控制，以检查细胞对多种反应的机制 定向迁移线索。细胞迁移在许多生理和病理过程中发挥着重要作用。 伤口愈合、发育和癌症侵袭等过程。迁徙常常不仅仅是随机的， 但通过识别对齐的细胞外基质纤维或硬度梯度来定向目标， 分别产生接触引导和杜罗塔斯。在许多生物学背景下，这些线索都会出现 同时，迫使细胞整合这些信息。例如，刚度梯度和对齐的 Colla- gen 在伤口床内产生以引导真皮成纤维细胞迁移。类似的纤维结构和颗粒 饮食刺激癌细胞迁移出肿瘤微环境和包括基质在内的正常细胞 和免疫细胞针对肿瘤微环境。虽然人们对细胞如何重新认识有深入的了解 尽管细胞对单个方向线索作出反应，但实际上我们对细胞如何整合多个线索和 根据该集成做出迁移决策。此外，有一种假设是接触指导 和 durotaxis 是重叠的定向细胞迁移机制，但这尚未经过严格的测试。 对多线索定向迁移的机制理解将需要对 F-如何 肌动蛋白和微管网络运行。事实上，一些证据表明，接触指导和 durotax- 它可能使用略有不同的 F-肌动蛋白网络结构，因为接触引导被认为是由 F- 控制的 肌动蛋白纤维结构，但杜罗轴不是。将采用工程方法来设计体外环境 允许在 2D 和 3D 环境中独立调整接触引导和 durotaxis。更远- 此外，F-肌动蛋白分支、成束和收缩的作用使细胞更喜欢排列的胶原纤维 将测试刚度的 gen 或梯度。这将揭示所涉及的共享或竞争分子途径 当这两个定向迁移线索单独或同时存在时。了解细胞如何Mi- 响应多种线索的格栅对包括组织工程在内的多个生物医学领域产生广泛影响 和疾病治疗。确定细胞如何在体外对多种线索做出反应将使我们能够预测细胞 伤口愈合、发育、癌症侵袭和免疫反应的反应导致候选药物的产生 例如癌症或增强伤口愈合和免疫反应的策略。