CELL/CELL AND MATRIX INTERACTIONS IN HEART MORPHOGENESIS

描述：1%的新生儿患有先天性心脏病 心脏缺如，常见于心脏的隔膜。尽管有这样的体检 重要的是，人们对细胞的分子基础知之甚少。 将心脏从未分化的细胞团转化为 单直的管子，然后变成四腔的结构。这些变化 一系列上皮-间充质转化的结果，其中 片状上皮细胞失去黏附，转化为迁移性间充质 细胞，并最终在空间和时间上调节分化 将图案转化为新的结构。这些研究的长期目标是 以确定参与这种细胞调控的特定分子 黏附以及这些黏附分子如何影响细胞行为。对这件事 最后，最近的研究集中在一类细胞外基质 蛋白质，细胞外硫酸软骨素蛋白多糖(CSPGs)，AS 在这些CSPG的细胞表面受体上。拟议中的实验 重点观察CSPG神经细胞与神经细胞之间的相互作用 细胞表面glycosyltransferaseN-acetylgalactosaminylphosphotransferase (GalNAcPTase)启动信号转导级联，间接地 抑制细胞间黏附分子N-钙粘附素的功能。一个 各种证据表明，这种相互作用可能 调节去黏附和随后的细胞迁移和分化 发生在上皮-间充质转化过程中 在心脏发育过程中起关键作用。 为了验证这一假设，我们将实现以下具体目标 执行：1)确定特定的多肽序列或 神经钙素中的寡糖参与其与GalNAcPTase的相互作用， 以及2)确定神经CaN-GalNAcPTase相互作用的后果 过程中发生的去黏附、细胞迁移和分化 心脏发育早期的上皮-间充质转化及其意义 涉及蛋白质酪氨酸磷酸化的信号转导机制。 这些实验将使用各种细胞生物学、分子 生物、生化和免疫学方法。潜在健康 这些研究的好处是能够识别和理解 先天性心脏病的分子基础及设计治疗策略 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.