Fine-Tuning the Notch Signaling Pathway via O-Glucosylation

通过 O-葡萄糖基化微调 Notch 信号通路

基本信息

批准号：
8628360
负责人：
Hamed Jafar-Nejad
金额：
$ 29.74万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8628360
关键词：
Adult Affect Animals Binding Biochemical Biological Assay Calcium ion Carbohydrates Cell Culture Techniques Cell Differentiation process Cell Line Cell Maintenance Cells Coculture Techniques Data Development Disease Drosophila genus Embryonic Development Enzymes Epidermal Growth Factor Equilibrium Extracellular Domain Future Gene Dosage Genetic Genetic Screening Glucose Glucosyltransferase Health Hematologic Neoplasms Hematopoietic stem cells Homeostasis Homologous Gene Human Human Development Inherited Learning Ligand Binding Ligands Light Link Malignant Neoplasms Mammalian Cell Mammals Mediating Memory Molecular Molecular Conformation Mouse Cell Line Mus Mutation Notch Signaling Pathway Oncogenic Organ Pathway interactions Patients Phenotype Play Polysaccharides Process Proteins Publishing Regenerative Medicine Regulation Role Sensory Signal Transduction Site Stem cells Suppressor Genes Testing Therapeutic Transgenic Organisms Tumor Angiogenesis Veins Wing Xylose angiogenesis base cell fate specification developmental disease extracellular fly human disease in vivo insight interest knock-down leukemia mouse model nervous system disorder notch protein overexpression protein protein interaction research study small hairpin RNA therapeutic target tool xylosyltransferase

项目摘要

DESCRIPTION (provided by applicant): Notch signaling in an evolutionarily conserved pathway that regulates diverse processes in animals, including stem cell maintenance, cell fate specification, learning and memory, and angiogenesis. Maintaining an optimal level of Notch signaling is essential for normal human development and human health, as mutations that result in increased or decreased activity of the Notch pathway cause a number of human diseases, including cancer and developmental disease. Moreover, therapeutic manipulation of the Notch pathway activity is of great interest in Notch-related diseases and in regenerative medicine. We have identified an evolutionarily conserved enzyme called Rumi, which adds O-linked glucose to specific EGF repeats of Notch receptors and regulates Notch signaling in both Drosophila and mammals. Our data indicate that the number and distribution of O-glucose residues on the Drosophila Notch determines the strength of Notch signaling over a wide range, and that mammalian Notch signaling is sensitive to Rumi gene dosage is specific contexts. Our preliminary data indicate that addition of one or two xylose residue to O-glucose by newly identified enzymes can further regulate Notch signaling. Our data strongly suggest that the level and distribution of O-glucose and its extended forms on Notch tightly regulate the strength of Notch signaling. We will elucidate the mechanisms underlying the fine-tuning of the Notch pathway by carbohydrates by using a combination of Drosophila genetics, cell-based signaling assays and biochemical experiments. In the long run, this project has the potential to establish tools to alter the activity of Notch signaling by manipulating the level of O-glucose and xylose on Notch proteins.

描述（由申请人提供）：在进化保守的途径中的Notch信号传导调节动物的各种过程，包括干细胞维持，细胞命运规范，学习和记忆和血管生成。保持最佳水平的Notch信号传导对于正常的人类发育和人类健康至关重要，因为突变导致Notch途径的增加或减少会导致许多人类疾病，包括癌症和发育疾病。此外，对Notch途径活性的治疗操作在与Notch相关的疾病和再生医学中引起了极大的兴趣。我们已经确定了一种称为Rumi的进化保守的酶，该酶在Notch受体的特定EGF重复序列中添加了O连接的葡萄糖，并调节果蝇和哺乳动物中的Notch信号传导。我们的数据表明，果蝇缺口上O-葡萄糖残基的数量和分布确定了在较大范围内Notch信号的强度，并且哺乳动物Notch信号对Rumi Gene剂量敏感是特定的环境。我们的初步数据表明，通过新鉴定的酶在O-葡萄糖中添加一个或两个木糖残基可以进一步调节Notch信号传导。我们的数据强烈表明O-葡萄糖的水平和分布及其在Notch上的扩展形式严格调节Notch信号的强度。我们将通过使用果蝇遗传学，基于细胞的信号分析和生化实验的组合来阐明碳水化合物对凹口通路进行微调的机制。从长远来看，该项目有可能通过操纵O-葡萄糖和木糖的水平来建立工具来改变Notch信号的活性。缺口蛋白。