Extracellular Matrix as a Solid-State Regulator During Angiogenesis

细胞外基质作为血管生成过程中的固态调节剂

• 批准号: 7313775
• 负责人: DONALD E INGBER
• 金额: $ 26.52万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7313775
• 关键词: Adhesions; Adhesives; Apoptosis; Area; Biomechanics; Blood Vessels; Blood capillaries; Calcium; Capillary Endothelial Cell; Cell Shape; Cell surface; Cells; Chemicals; Coupling; Cues; Cytoskeletal Modeling; Development; ECM receptor; Endothelial Cells; Equilibrium; Exhibits; Extracellular Matrix; Focal Adhesions; Gene Expression; Goals; Grant; Growth; In Vitro; Individual; Integrins; Ion Channel; Lead; Link; Location; Malignant Neoplasms; Mechanics; Modeling; Molecular; Molecular Target; Monomeric GTP-Binding Proteins; Positioning Attribute; Process; Proteins; Role; Signal Transduction; Signaling Molecule; Solid; Stress; TFII Transcription Factors; Therapeutic Intervention; Traction; Tumor Angiogenesis; Variant; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Work; angiogenesis; base; capillary; cell behavior; cell growth; cell motility; clinically relevant; directional cell; in vivo; inhibitor/antagonist; migration; millisecond; paxillin; receptor; research study; response; rho; solid state; tumor

The general goal of this renewal proposal is to understand the biomechanical mechanism by which extracellular matrix (ECM) regulates angiogenesis during tumor development, with a specific focus on how physical interactions between capillary endothelial (CE) cells and their ECM adhesions control directional cell motility. During the last grant period, we showed that mechanical changes at the cell-ECM interface govern the direction in which cells move because local variations of physical force distributions dictate where cells will form focal adhesions (FAs) and extend new motile processes when stimulated with soluble motility factors. Analysis of this motility steering mechanism and the mechanism of FA repositioning revealed a central role for transfer of mechanical forces across transmembrane integrin receptors which elicit signaling responses that, in turn, activate additional p1 integrin receptors. Other signaling molecules, including the small GTPases, Rho and Rac, also contribute to the mechanism by which ECM influences FA location, and cells that lack the FA protein paxillin fail to exhibit spatial coupling between FA formation and lamellipodia extension. In separate studies, we discovered that an upstream regulator of Rho, p190RhoGAP, may link cytoskeletal signaling to cell motility and angiogenesis by another mechanism: this Rho inhibitor regulates the activity of the transcription factor TFII-I and thereby controls expression of the vascular endothelial growth factor (VEGF) receptor VEGFR2. Thus, the specific aims include: 1) To explore how stress- dependent activation of (31 integrin and Rho alter focal adhesion position, 2) To determine how focal adhesions govern lamellipodia positioning and directional cell migration, and 3) To analyze how cytoskeletal signaling through p190RhoGAP influences VEGFR2 gene expression. These studies will include in vitro mechanistic experiments as well as in vivo studies in a tumor angiogenesis model to determine the potential clinical relevance of our findings. Understanding the molecular basis of this mechanical signaling response that controls direction migration of capillary blood vessel cells could lead to identification of new molecular targets for therapeutic intervention in virtually all solid cancers that require continuous angiogenesis for their own growth and expansion.

这项更新建议的总体目标是了解生物力学机制， 细胞外基质（ECM）在肿瘤发展过程中调节血管生成，特别关注如何 毛细血管内皮（CE）细胞与其ECM粘附之间的物理相互作用控制定向细胞 能动性在上一个资助期间，我们发现细胞-ECM界面的机械变化决定了细胞的生长。 细胞移动的方向，因为物理力分布的局部变化决定了细胞的位置， 当用可溶性运动刺激时，将形成局灶性粘连（FA）并延长新的运动过程 因素对这种动力转向机制和FA重新定位机制的分析揭示了一种 跨膜整合素受体机械力传递的中心作用 这些反应反过来激活另外的β 1整联蛋白受体。其他信号分子，包括 小GTP酶Rho和Rac也有助于ECM影响FA定位的机制， 缺乏FA蛋白桩蛋白的细胞不能表现出FA形成和板状伪足之间的空间耦合 扩展名.在单独的研究中，我们发现Rho的上游调节因子p190 RhoGAP可能与Rho的表达相关。 细胞骨架信号传导通过另一种机制影响细胞运动和血管生成：这种Rho抑制剂调节 转录因子TFII-I的活性，从而控制血管内皮细胞的表达， 生长因子（VEGF）受体VEGFR 2。因此，本研究的具体目标包括：1）探讨压力- β 1整合素和Rho的依赖性活化改变粘着斑位置，2）为了确定粘着斑如何与细胞粘附， 粘附控制板状伪足定位和定向细胞迁移，和3）为了分析细胞骨架如何 通过p190 RhoGAP的信号传导影响VEGFR 2基因表达。这些研究将包括体外 机制实验以及在肿瘤血管生成模型中的体内研究，以确定 我们的发现的临床意义。 了解这种控制方向迁移的机械信号反应的分子基础 毛细血管细胞的研究可能导致识别新的分子靶点进行治疗干预 在几乎所有需要持续血管生成来进行自身生长和扩张的实体癌中。