Adult Tissue Morphogenesis: Functinoal Regulation of Intussusceptive Antiogenesis

成人组织形态发生：肠套叠抗发生的功能调节

• 批准号: 7898872
• 负责人: STEVEN MENTZER
• 金额: $ 39.56万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898872
• 关键词: 3-Dimensional; Address; Adult; Anatomy; Angiogenic Factor; Blood Vessels; Blood capillaries; Blood flow; Chemical Exposure; Chronic; Colitis; Colon; Corrosion Casting; Data; Development; Disease; Embryo; Endothelial Cells; Experimental Designs; Gene Expression; Gene Expression Profile; Goals; Growth; Image; In Vitro; Inflammation; Inflammation Process; Inflammatory; Inflammatory Infiltrate; Injury; Location; Maps; Measures; Mediator of activation protein; Methods; Modeling; Molecular; Morphogenesis; Mus; Natural regeneration; Organ; Pathway interactions; Pattern; Photochemotherapy; Physiological; Process; Regenerative Medicine; Regulation; Scanning Electron Microscopy; Signal Pathway; Solid; Staging; Structure; Testing; Tissue Engineering; Tissues; Tracer; Vascular blood supply; Wound Healing; angiogenesis; base; capillary; density; injured; interdisciplinary approach; intravital microscopy; laser capture microdissection; public health relevance; response; simulation; technique development

DESCRIPTION (provided by applicant): Inflammation-induced angiogenesis is a fundamental biologic process relevant to chronic inflammatory diseases, wound healing and tissue engineering. In these settings, a process that could rapidly expand capillary density would be of fundamental importance. To address this need, we have developed a murine colon model in which chemically-induced inflammation triggers intussusceptive (nonsprouting) angiogenesis. Previously considered a developmental phenomenon, intussusceptive angiogenesis is an underappreciated process in adult organs. Intussusceptive angiogenesis can rapidly expand capillary networks by the active subdivision of one vessel into two lumens. In our adult colon model, the earliest stage of intussusceptive angiogenesis is the formation of intraluminal "pillars." Demonstrated by corrosion casting and 3-dimensional scanning electron microscopy (SEM), the pillars form within 7 days after chemical exposure. SEM demonstrates that the pillars are nonrandomly distributed at vessel junctions within the colon mucosal plexus. Over the next 3 weeks, the physical extension of the pillar down the luminal axis of the vessel results in capillary replication. Intravital microscopy of the mucosal plexus during this period demonstrates perturbed blood flow patterns including focally increased volumetric flow and oscillating flow. Our hypothesis is that these intravascular flow fields regulate the process of intussusceptive angiogenesis. Our long-term goal is to understand the dynamic interaction between intravascular blood flow and the molecular regulation of intussusceptive angiogenesis. To test our hypothesis, we have developed a multidisciplinary approach that integrates structural anatomy, intravital microscopy and computation flow modeling. Our specific aims will test the hypothesis using the following approach: 1) Measure microvessel structure and blood flow patterns in the inflamed mucosal plexus; 2) Model blood flow patterns during intussusceptive angiogenesis using computational flow simulations; 3) Map gene expression within the mucosal plexus using laser capture microdissection. The long-term goal of this project is an understanding of the dynamic interaction between intravascular blood flow and the molecular regulation of intussusceptive angiogenesis. PUBLIC HEALTH RELEVANCE: This project investigates the regulation of intussusceptive angiogenesis-a process of blood vessel replication that rapidly expands pre-existing vascular networks. The development of techniques and methods that can rapidly expand blood supply to injured tissue will have a significant impact on regenerative medicine and tissue engineering.

描述（由申请人提供）：炎症引起的血管生成是与慢性炎性疾病，伤口愈合和组织工程有关的基本生物学过程。在这些情况下，可以快速扩大毛细管密度的过程将至关重要。为了满足这一需求，我们开发了一种鼠结肠模型，在该模型中，化学诱导的炎症会触发肠胃ut乱的（非刺激）血管生成。先前被认为是发育现象，肠use依的血管生成是成年器官中的一个未充分考虑的过程。通过将一个容器的主动细分分成两个流明，肠us依的血管生成可以迅速扩展毛细血管网络。在我们的成年结肠模型中，最早的肠内血管生成的阶段是形成腔内“支柱”。通过腐蚀铸造和3维扫描电子显微镜（SEM）证明，在化学暴露后的7天内形成了支柱。 SEM证明，这些支柱是非随机分布在结肠粘膜丛内的血管连接处。在接下来的3周内，支柱向下的物理延伸沿血管的腔轴延伸会导致毛细管复制。在此期间，粘膜神经丛的插入显微镜表明，血液流动模式，包括局部增加的体积流量和振荡流。我们的假设是这些血管内流场调节了肠us依的血管生成过程。我们的长期目标是了解血管内血流与肠内血管生成的分子调节之间的动态相互作用。为了检验我们的假设，我们开发了一种多学科方法，该方法整合了结构解剖学，插入式显微镜和计算流程模型。我们的具体目的将使用以下方法检验假设：1）测量发炎粘膜丛中的微血管结构和血流模式； 2）使用计算流仿真在肠use依的血管生成过程中模拟血流模式； 3）使用激光捕获显微解剖在粘膜丛中地图基因表达。该项目的长期目标是了解血管内血流之间的动态相互作用与肠内血管生成的分子调节之间的动态相互作用。公共卫生相关性：该项目调查了对肠胃敏感性血管生成的调节 - 血管复制的过程，迅速扩大了先前存在的血管网络。可以快速将血液供应扩大到受伤组织的技术和方法的发展将对再生医学和组织工程产生重大影响。