Molecular Roles of Syndecans in Development

多聚糖在发育中的分子作用

• 批准号: 7009598
• 负责人: H. Joseph Yost
• 金额: $ 36.5万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7009598
• 关键词: Xenopus oocyte; biological signal transduction; cardiogenesis; cell cell interaction; cell migration; enzyme activity; extracellular matrix; gap junctions; hydrogen potassium exchanging ATPase; immunoprecipitation; mesoderm; nonmammalian vertebrate embryology; phosphorylation; protein kinase C; protein localization; protein structure function; syndecan

DESCRIPTION (provided by applicant): During early embryogenesis in all vertebrates, bilateral symmetry is broken to give rise to the embryonic Left-Right axis. LR information is transmitted to a wide variety of developing organ primordia, including the heart. Although significant advances have been made in our understanding of a complex set of pathways that control intermediate steps in LR development, the genes, molecular and cellular mechanisms responsible for the initiation of the LR axis are unknown. Syndecan-2 is a single-pass transmembrane heparan sulfate proteoglycan. We recently found that one of the earliest steps in LR development is mediated through Protein Kinase C gamma (PKCgamma)-dependent asymmetric phosphorylation of Syndecan-2. This initiates a novel "inside-out" signaling pathway, in which asymmetrically phosphorylated Syndecan-2 transduces LR information from ectoderm cells to migrating mesoderm cells during early gastrulation. The research in this proposal will elucidate the molecular pathways that initiate LR asymmetry in syndecan function and the mechanisms by which syndecan-2 can send at least two distinct signals (left or right) to migratory cells. Besides LR development, the proposed research will elucidate two other roles for syndecan-2: it regulates fibronectin fibrillogenesis, by forming a signaling complex with PINCH and integrin, and it is capable of re-orienting the direction of migrating mesoderm cells. The long-term goal of this research is to significantly increase our understanding of the genes and mechanisms that control cardiovascular development, cell-cell signaling, extracellular matrix formation, and cell migration. The principles derived from this research will be applicable to a wide range of cell-cell signaling events in development and disease.

描述（由申请人提供）：在所有脊椎动物的早期胚胎发生过程中，双侧对称性被打破以产生胚胎左右轴。 LR信息被传输到包括心脏在内的各种发育中的器官原始。尽管我们对控制LR发育中的中间步骤的一组复杂途径的理解已经取得了重大进展，但导致LR轴启动的基因，分子和细胞机制尚不清楚。 Syndecan-2是单个跨膜硫酸肝素蛋白聚糖。我们最近发现，LR发育中最早的步骤之一是通过蛋白激酶C伽马（PKCGAMMA）依赖性的syndecan-2的不对称磷酸化介导的。这启动了一种新型的“内部”信号通路，其中不对称磷酸化的syndecan-2将LR信息从外胚层细胞转导到早期胃肠后迁移中胚层细胞。该提案中的研究将阐明syndecan函数中启动LR不对称性的分子途径以及Syndecan-2可以将至少两个不同的信号（左或右）发送到迁移细胞的机制。除了LR的发展外，拟议的研究还将阐明Syndecan-2的其他两个角色：它通过与Pinch and Iltecin形成信号传导复合物来调节纤连蛋白原纤维生成，并且能够重新定位迁移中胚层细胞的方向。 这项研究的长期目标是显着提高我们对控制心血管发育，细胞信号传导，细胞外基质形成和细胞迁移的基因和机制的理解。从这项研究中得出的原理将适用于发育和疾病中的各种细胞细胞信号传导事件。