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: 6623982
• 负责人: SCOTT B SELLECK
• 金额: $ 25.25万
• 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/6623982
• 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.

描述(申请人提供)：细胞表面蛋白多糖 在生长因子信号的组织选择性调节中的作用。 目前的证据表明，蛋白多糖控制着生长的组装 细胞表面的因子配体-受体复合体。Glypicans代表一种 完整的膜蛋白多糖家族，其特征是与 质膜外叶和硫酸肝素修饰。一 人类GPC3因其在调节身体大小方面的作用而引人注目 和肿瘤的发展。Glypicans在脊椎动物中也广泛表达 神经系统，尽管对它们在这一组织中的功能一无所知。 这个项目的长期目标是了解不同的分子 龟头虫的功能，包括它们参与生长控制、肿瘤 利用基因和分子工具抑制和神经系统发育 在果蝇中有，果蝇黑腹果蝇。 我们已经确定了影响这两个英国人编码基因的突变。 在果蝇中，分裂不正常地延迟(每天)，并且每天类似。我们的 最近的研究表明，日常生活和日常生活会影响组织和细胞 生长至少部分受胰岛素样生长因子信号的调节。 我们还在中枢神经系统发现了轴突发生缺陷。 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 观察是我们具体目标的基础：目标1.确定 在细胞和组织的生长控制中每日和每日的分子活性。 目的2.研究DAY和DAY-LIKE介导的分子机制 抑制果蝇S2细胞的胰岛素反应。目标3.确定 日常型胚胎轴突投射缺陷的分子和细胞基础 变种人。目的4.建立石杉和石杉的分子基础 糖胺多聚糖在突触组装中的作用。