HYALURONAN IN LIMB MORPHOGENESIS

透明质酸在肢体形态发生中的作用

• 批准号: 6911939
• 负责人: ROBERT A KOSHER
• 金额: $ 26.19万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6911939
• 关键词: apical membrane; biological signal transduction; carbohydrate metabolism; cartilage development; cell differentiation; cell migration; cell proliferation; epidermal growth factor; extracellular matrix; growth factor receptors; histogenesis; hyaluronate; limbs; mesenchyme; tissue /cell culture

The goal of this is to elucidate the functions of the extracellular matrix and cell surface macromolecule hyaluronan (HA) in vertebrate limb morphogenesis. HA is a huge linear glycosaminoglycan which occupies an extensive molecular domain and has a pronounced hydration capacity. HA promotes the migration and proliferation of cells in a variety of model systems, and the binding of HA to its cell surface receptors including CD44 can also activate intracellular signaling. HA has recently been implicated as a costimulator of the EGFR/ErbB signaling network, which is a signaling pathway involved limb morphogenesis and patterning. The distal subapical mesenchymal cells of the developing limb bud, which are undergoing proliferation and patterning in response to the apical ectodermal ridge (AER) and other signaling centers, produce high amounts of HA which forms an expansive hydrated extracellular matrix between the cells. Thus, the cell and tissue interactions controlling the outgrowth and patterning of the limb occur in an environment rich in extracellular and pericellular HA. Based on its role in stimulating proliferation, migration, and intracellular signaling in many other systems, the hypothesis that HA facilitates the proliferation and directed migration of the subapical mesenchymal cells in response to the AER will be investigated, as will the hypothesis that HA modulates one or more of the signaling pathways particularly the EGFR/ErbB signaling network that regulates limb patterning events in the subapical mesoderm. As the mesenchymal cells in the central core of the limb bud become located outside of the range of AER signaling, HA production declines to low levels and extracellular HA is removed. The hypothesis that this downregulation of HA synthesis and removal of extracellular HA is necessary for the cells to form the precartilage condensations that trigger chondrogenic differentiation will be investigated. HA is also synthesized in relatively high amounts by the AER. The hypothesis that HA secreted by the AER may play an important role in facilitating the AER-subridge mesoderm interactions that result in directed limb outgrowth will be investigated.

其目的是阐明细胞外基质和细胞表面的功能。 大分子透明质酸(HA)与脊椎动物肢体形态发生透明质酸是一种巨大的直链糖胺多聚糖，具有广泛的分子结构域和显著的水化能力。在许多模型系统中，HA促进细胞的迁移和增殖，HA与包括CD44在内的细胞表面受体的结合也可以激活细胞内信号转导。最近，HA被认为是EGFR/ErbB信号网络的共刺激因子，EGFR/ErbB信号网络是一条涉及肢体形态发生和图案形成的信号通路。发育中的肢芽的远端尖下间充质细胞 顶端外胚层脊(AER)和其他信号中心的增殖和图案化反应产生了大量的HA，在细胞之间形成了一种膨胀的水合细胞外基质。因此，控制肢体生长和图案的细胞和组织相互作用发生在富含细胞外和细胞外HA的环境中。基于其在许多其他系统中刺激增殖、迁移和细胞内信号传递的作用，将研究HA促进AER反应的根尖下间充质细胞的增殖和定向迁移的假设，以及HA调节一个或多个信号通路特别是调节根尖下中胚层中肢体图案事件的EGFR/ErbB信号网络的假说。当肢芽中央核心的间充质细胞位于AER信号范围之外时， HA产量下降到低水平，胞外HA被去除。假设这一点 下调HA合成和清除细胞外HA对于细胞形成触发软骨分化的软骨前凝聚是必要的，将进行研究。AER也合成了相对较高数量的HA。AER分泌的HA可能在促进AER-亚脊中胚层相互作用导致定向肢体生长方面发挥重要作用的假说将被调查。