Cell-Cell and Cell-Matrix Interactions in Morphogenesis

形态发生中的细胞-细胞和细胞-基质相互作用

• 批准号: 10387759
• 负责人: DOUGLAS W. DESIMONE
• 金额: $ 12.5万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387759
• 关键词: Actins; Adherens Junction; Adhesions; Adult; Amphibia; Anatomy; Applications Grants; Area; Biological Assay; Biology; Cadherins; Cell Adhesion; Cell model; Cell-Matrix Junction; Cells; Complex; Congenital Abnormality; Cytoskeleton; Desmosomes; Development; Developmental Process; Disease; Elements; Embryonic Development; Engineering; Extracellular Matrix; Focal Adhesions; Future; Genes; Goals; Human; Individual; Integrins; Intermediate Filaments; Keratin; Laboratories; Link; Mesoderm; Methods; Morphogenesis; Movement; Organ; Pattern; Process; Proteins; Regulation; Role; Shapes; Site; Stress; Testing; Tissues; Translational Research; Work; Xenopus; base; body system; cell motility; design; experimental study; extracellular; gastrulation; in silico; mechanical force; mechanotransduction; migration; morphogens; novel; recruit; replacement tissue; simulation; synergism; tissue regeneration; tissue-level behavior; wound healing

Morphogenesis is the fundamental developmental process that drives tissue assembly and elaborates the diverse anatomical structures that together comprise the body plans of all metazoa. Most human birth defects arise from disruptions in normal morphogenetic processes. How morphogenesis works at multiple levels of organization and complexity is one of the key remaining questions in biology and progress in this area will be needed to help inform efforts to engineer replacement tissues and organs. For nearly three decades our laboratory has approached this problem by focusing on the cell movements and tissue rearrangements responsible for gastrulation in the amphibian Xenopus. We explore how cell adhesion to other cells and to the extracellular matrix (ECM) is regulated to promote or stabilize the cell and tissue movements of gastrulation. Cadherin and integrin adhesion complexes are central players in these processes and aside from their general roles in holding cells and tissues together, they also sense, resist and distribute mechanical forces that arise as a consequence of morphogenesis. We have discovered a novel function for cadherins and keratin intermediate filaments (KIF) in the force-dependent regulation of collective cell migration in the mesendoderm at gastrulation. Although the importance of adherens junctions, focal adhesions and the actin cytoskeleton to mechanosensation and mechanotransduction is now well established, the role of desmosomes and other intermediate filament (IF) associated junctions in these processes has been largely overlooked. A major goal of this grant proposal is to bridge this significant gap in understanding by focusing on KIF functions and the association of the KIF cytoskeleton with cadherin-based adhesions in the mesendoderm. We hypothesize that the magnitude of forces applied to cadherins can direct the differential recruitment and assembly of adhesions linked to the actin or KIF cytoskeletons. We will test this by developing new assays designed to apply defined forces to cadherins on single cells and follow the recruitment of adherens- and desmosomal-associated junctional proteins to stressed adhesion sites. In related experiments we will also ask whether patterning of mesoderm genes varies with the magnitude of forces applied to cell-cell and/or cell-matrix adhesions, perhaps acting analogously to (and/or in synergy with) cells sensing positional information within a concentration gradient of morphogen. Future progress in these areas will also benefit from the development of in silico simulations of morphogenetic movements. A team of collaborators expert in agent-based and finite element methods for modelling cell and tissue-level behaviors will work with us to simulate initially the force dependent polarization and collective migration of mesendoderm cells. Our longer-term goal is to explore ways to integrate simulations of multiple regional morphogenetic machines to gain a better picture of the global contributions of individual tissue movements to gastrulation.

形态发生是驱动组织组装并阐述的基本发育过程 各种解剖结构共同构成了所有后生的身体计划。大多数人的先天缺陷 是由正常形态发生过程中的破坏引起的。形态发生如何在多个层次上起作用 组织和复杂性是生物学和该领域进步的关键问题之一 需要帮助努力设计替换组织和器官的努力。近三十年来 实验室通过关注细胞运动和组织重排来解决这个问题 负责两栖动物的胃肠道。我们探索细胞对其他细胞的粘附以及对 细胞外基质（ECM）受调节以促进或稳定胃的细胞和组织运动。 钙粘蛋白和整联蛋白粘附复合物是这些过程中的核心参与者，除了一般性 它们在将细胞和组织保持在一起中的作用，它们还感知，抵抗和分布出现的机械力 形态发生的结果。我们发现了钙粘蛋白和角蛋白中间体的新功能 在胃胃胚层中集体细胞迁移的力依赖性调节中细丝（KIF）。 虽然粘附连接，焦点粘连和肌动蛋白细胞骨架对机械敏感的重要性 现在已经建立了机械转导的机械转导，脱骨体和其他中间丝的作用（if） 这些过程中的相关连接在很大程度上被忽略了。该赠款建议的主要目标是 通过关注KIF功能和KIF的关联来弥合理解的重大差距 梅甲胚层中具有基于钙粘着蛋白的粘附的细胞骨架。我们假设力的大小 应用于钙粘蛋白可以指导与肌动蛋白或KIF相关的粘附的差异募集和组装 细胞骨架。我们将通过开发旨在将定义的力应用于钙粘蛋白的新测定法来测试这一点 单细胞并跟随粘附剂和脱染色体相关的连接蛋白募集到应力 粘附位点。在相关实验中，我们还将询问中胚层基因的图案是否随着 应用于细胞细胞和/或细胞矩阵粘附的力的大小，也许与（和/或 与）细胞在形态学的浓度梯度中感测位置信息的协同作用。未来的进步 在这些领域，也将受益于形态发生运动的计算机模拟的发展。一个 基于代理和有限元方法的合作者团队，用于建模细胞和组织级别 行为将与我们合作，以模拟最初的依赖性两极分化和集体迁移 中胚层细胞。我们的长期目标是探索整合多个区域模拟的方法 形态发生的机器可以更好地了解单个组织运动的全球贡献 胃。