CELL/CELL AND MATRIX INTERACTIONS IN HEART MORPHOGENESIS

描述：百分之一的新生儿患有先天性心脏病。 通常在心脏分隔处的缺陷。 尽管医疗 重要的是，对细胞的分子基础知之甚少。 将心脏从一团未分化的细胞转化为 单直管，然后到四室结构。 这些变化 由一系列上皮-间充质转化引起， 片状上皮细胞失去粘附，转化为迁移性间充质细胞 细胞，并最终分化在空间和时间调节 将模式转化为新颖的结构。 这些研究的长期目标是 为了确定参与这种细胞调节的特定分子， 粘附以及这些粘附分子如何影响细胞行为。 本 最后，最近的研究集中在一类细胞外基质 蛋白质，大细胞外硫酸软骨素蛋白聚糖（CSPG）， 对这些CSPG的细胞表面受体有很好的作用。 拟议的实验 集中于观察到CSPG神经聚糖与 细胞表面糖基转移酶 （GalNAcPT酶）启动信号转导级联，间接 抑制细胞间粘附分子N-钙粘蛋白的功能。 一 各种证据表明，这种相互作用可能 调节去粘附和随后的细胞迁移和分化 发生在上皮间质转化的过程中， 对心脏发育至关重要 为了检验这一假设，将实现以下具体目标： 进行：1）确定特定多肽序列或 神经聚糖中的寡糖参与其与GalNAcPT酶的相互作用， 和2）确定神经聚糖-GalNAcPT酶相互作用对神经细胞的影响。 细胞的去粘附、迁移和分化， 心脏发育早期的上皮-间质转化 涉及蛋白质酪氨酸磷酸化的信号转导机制。 这些实验将使用多种细胞生物学、分子生物学、 生物学、生物化学和免疫学方法。 潜在健康 这些研究的好处是能够认识和理解 先天性心脏病的分子基础，并设计策略， 纠正这些缺陷。

DESCRIPTION: One percent of newborn humans have some congenital heart defect, usually in the septation of the heart. Despite this medical importance, little is known about the molecular bases for the cellular processes that convert the heart from an undifferentiated mass of cells to a single straight tube and then to a four-chambered structure. These changes results from a series of epithelial-mesenchymal transformations wherein epithelial cells in sheets lose adhesion , convert to migrating mesenchymal cells, and finally differentiate in spatially and temporally regulated patterns into novel structures. The long-term objective of these studies is to identify the specific molecules involved in this regulation of cellular adhesion and how these adhesion molecules affect cell behavior. To this end, recent studies have focussed on a class of extracellular matrix proteins, large extracellular chondroitin sulfate proteoglycans (CSPGs), as well on cell-surface receptors for these CSPGs. the proposed experiments focus on the observation that the interaction of the CSPG neurocan with the cell surface glycosyltransferaseN-acetylgalactosaminylphosphotransferase (GalNAcPTase) initiates a signal transduction cascade that indirectly inhibits the function of the cell-cell adhesion molecule N-cadherin. A variety of evidence suggests the hypothesis that this interaction may regulate the de-adhesion and subsequent cell migration and differentiation that occurs during one of the epithelial-mesenchymal transformations that are critical in heart development. In order to test this hypothesis, the following specific aims will be performed: 1) Determine the specific polypeptide sequences or oligosaccharides in neurocan involved in its interaction with GalNAcPTase, and 2) Determine the consequences of neurocan-GalNAcPTase interactions on the de-adhesion, cell migration, and differentiation that occur during epithelial-mesenchymal transformations in early heart development and on signal transduction mechanisms involving protein tyrosine phosphorylation. These experiments will use a variety of cell biological, molecular biological, biochemical, and immunological methods. Potential health benefits of these studies are the ability to recognize and understand the molecular bases of congenital heart defects and to design strategies to correct these defects.