PROTEOGLYCANS IN GROWTH FACTOR SIGNALING AND DEVELOPMENT

生长因子信号传导和发育中的蛋白聚糖

• 批准号: 6683754
• 负责人: SCOTT B SELLECK
• 金额: $ 16.41万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6683754
• 关键词: Drosophilidae; arthropod genetics; axon; biological signal transduction; cell cycle; cell growth regulation; developmental genetics; developmental neurobiology; gene expression; growth factor receptors; molecular dynamics; mucopolysaccharides; neurogenesis; protein structure function; proteoglycan; site directed mutagenesis; synaptogenesis; tissue /cell culture; transmission electron microscopy; tumor suppressor proteins

DESCRIPTION (PROVIDED BY APPLICANT): Cell surface proteoglycans serve critical functions in the tissue-selective regulation of growth factor signaling. Current evidence indicates that proteoglycans control the assembly of growth factor ligand-receptor complexes at the cell surface. Glypicans represent one family of integral membrane proteoglycans, characterized by a GPIlinkage to the outer leaflet of the plasma membrane and heparan sulfate modification. One human glypican, GPC3, is remarkable for its role in the regulation of body size and tumor development. Glypicans are also widely expressed in the vertebrate nervous system, although nothing is known about their function in this tissue. The long term goals of this project are to understand the diverse molecular functions of glypicans, including their involvement in growth control, tumor suppression, and nervous system development using genetic and molecular tools available in the fruitfly, Drosophila melanogaster. We have identified mutations affecting both of the two glypican encoding genes in Drosophila, division abnormally delayed (daily), and daily-like (dly). Our recent studies have shown that daily and daily-like affect tissue and cell growth at least in part by regulation of Insulin-like growth factor signaling. We have also uncovered axonogenesis defects in the central nervous system of dly mutants. Finally, we have determined that glycosaminoglycan biosynthesis is critical for assembly of the neuromuscular synapse in Drosophila. These observations serve as the basis of our specific aims: Aim 1. Determine the molecular activity of daily and daily-like in cell and tissue growth control. Aim 2. Examine the molecular mechanisms of Daily and Daily-like mediated inhibition of insulin responses in Drosophila S2 cells. Aim 3. Determine the molecular and cellular basis of embryonic axon projection defects in daily-like mutants. Aim 4. Establish the molecular basis for glypican and glycosaminoglycan function in synapse assembly.

性状（由申请人提供）：细胞表面蛋白聚糖起关键作用 在生长因子信号传导的组织选择性调节中发挥作用。 目前的证据表明，蛋白聚糖控制的增长组装 在细胞表面的因子配体-受体复合物。Glypicans代表一个 完整的膜蛋白聚糖家族，其特征在于与膜蛋白聚糖的GPI连接。 质膜的外小叶和硫酸乙酰肝素修饰。一 人磷脂酰肌醇蛋白聚糖，GPC 3，因其在调节身体大小中的作用而引人注目 和肿瘤的发展。磷脂酰肌醇蛋白聚糖在脊椎动物中也广泛表达 神经系统，尽管对它们在该组织中的功能一无所知。 该项目的长期目标是了解不同的分子 磷脂酰肌醇蛋白聚糖的功能，包括它们参与生长控制、肿瘤 抑制和神经系统发育的基因和分子工具 在果蝇，黑腹果蝇中也有。 我们已经确定了影响两个磷脂酰肌醇蛋白聚糖编码基因的突变 在果蝇中，分裂异常延迟（每日）和每日样（dly）。我们 最近的研究表明，日常和日常样影响组织和细胞， 生长至少部分通过调节胰岛素样生长因子信号传导。 我们还发现了中枢神经系统中的轴突生成缺陷， dly变种人。最后，我们确定了糖胺聚糖的生物合成是 对果蝇神经肌肉突触的组装至关重要。这些 这些观察结果是我们具体目标的基础：目标1。确定 分子活性的日常和日常样在细胞和组织生长控制。 目标2.研究日常和日常样介导的分子机制 抑制果蝇S2细胞中的胰岛素反应。目标3.确定 胚胎轴突投射缺陷的分子和细胞基础 变种人目标4。建立磷脂酰肌醇蛋白聚糖的分子基础 糖胺聚糖在突触组装中的功能。