Genetic Control of Limb Development

项目描述（申请人提供）：该项目的目的是研究发育中的脊椎动物肢体的生长、模式化和再生的分子调控。在项目1中，将研究细胞外大分子透明质酸（HA）促进肢体间充质细胞响应于顶端外胚层嵴（AER）的生长、增殖和定向迁移的假设，以及HA与EGFR/ErbB信号网络在肢体生长和模式调节中协同作用的假设。还将研究HA在调节肢体软骨分化的发生中的作用，以及其在AER活性中的作用。在项目2中，EGFR/ErbB家族酪氨酸激酶受体和配体在AER的形成和功能中的作用，以及在控制沿着前后和背腹轴的肢体模式的信号传导通路中的作用将被研究，EGFR/ErbB信号传导在参与塑造肢体轮廓的程序性细胞死亡中的作用也将被研究。在项目3中，将研究调控胚胎小鼠肢芽中的指尖再生和鸡肢芽的AER依赖性再生的细胞和分子机制。特别是，定向细胞迁移和分化细胞粘附在再生反应中的作用将被研究，Dlx基因，Msx基因，BMP信号传导，FGF，EGFR/ErbB信号传导和透明质酸在哺乳动物趾尖和鸡肢芽再生控制中的作用和关系也将被研究。这些项目将由一个行政核心（核心A）提供支持，该核心将管理研究预算的财务方面。

DESCRIPTION (provided by applicant): The objective of the Program is to study the molecular regulation of the outgrowth, patterning, and regeneration of the developing vertebrate limb. In Project 1, the hypothesis that the extracellular macromolecule hyaluronan (HA) facilitates the outgrowth, proliferation, and directed migration of limb mesenchymal cells in response to the apical ectodermal ridge (AER) will be investigated, as will the hypothesis that HA acts in concert with the EGFR/ErbB signaling network in the regulation of limb outgrowth and patterning. The role of HA in regulating the onset of limb cartilage differentiation will also be studied, as will its role in AER activity. In Project 2, the roles of the EGFR/ErbB family of tyrosine kinase receptors and ligands in the formation and function of the AER and in the signaling pathways that control limb patterning along the anteroposterior and dorsoventral axes will be investigated, as will role of EGFR/ErbB signaling in the programmed cell death involved in shaping limb contours. In Project 3, the cellular and molecular mechanisms that regulate digit tip regeneration in the embryonic mouse limb bud and the AER-dependent regeneration of the chick limb bud will be studied. In particular, the roles of directed cell migration and differential cell adhesion in the regeneration response will be investigated, as will the roles and relationships among Dlx genes, Msx genes, BMP signaling, FGFs, EGFR/ErbB signaling, and hyaluronan in the control of mammalian digit tip and chick limb bud regeneration. The Projects will be supported by an Administrative Core (Core A) that will manage the financial aspects of the research budgets.