Regulation of Granulopoiesis by Fucosylation-Dependent Notch Signaling

通过岩藻糖基化依赖性Notch信号传导调节粒细胞生成

• 批准号: 8080204
• 负责人: Lan Zhou
• 金额: $ 12.78万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-10 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8080204
• 关键词: Animals; Applications Grants; Binding; Bone Marrow; Bone Marrow Transplantation; Cells; Chronic Myeloproliferative Disorder; Development; Dietary Supplementation; EGF gene; Environment; Enzymes; Fucose; Fucosyltransferase; Fucosyltransferase 1; Future; Glycoproteins; Goals; Granulopoiesis; Guanosine Diphosphate Fucose; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Homeostasis; Human; In Vitro; K-Series Research Career Programs; Laser Scanning Microscopy; Ligands; Link; Lymphoid; Lymphopoiesis; Marrow; Mediating; Membrane; Mus; Myelogenous; Myeloid Progenitor Cells; Myelopoiesis; Myeloproliferation; Neutrophilia; Notch Signaling Pathway; Outcome Study; Pathway interactions; Peripheral; Phenotype; Play; Polysaccharides; Process; Proteins; Quality Control; Regulation; Reporter; Research; Research Personnel; Role; Series; Signal Transduction; Signal Transduction Pathway; Specific qualifier value; Stem cells; Stromal Cells; Surface; Testing; Transgenic Organisms; Universities; Work; base; cell fate specification; dosage; embryonic stem cell; extracellular; in vitro Assay; in vivo; insight; mutant; neutrophil; notch protein; progenitor; programs; research study; self-renewal; stem; thymic hypoplasia; two-photon

DESCRIPTION (provided by applicant): The overall goal of this grant application is to support a K08 career development award that focuses on studying the role of the fucosylation-dependent Notch signaling pathway in the regulation of myeloid fate specification and myeloid lineage development. Fucosylated glycans are implicated in many bilogical processes. Fucosylation as O-linked fucose moieties on Notch extracellular EGF repeats is required for Notch signaling in various types of cell fate specification. Lan Zhou, the principle investigator of this proposal, in her previous work with Dr. John Lowe, and in her research conducted at Case Western Reserve University, identified a myeloproliferative phenotype in FX-/- mice, which are conditionally deficient in cellular fucosylation, is consequent to loss of Notch-dependent signal transduction on myeloid progenitor cells. In this proposal, Dr. Zhou will use a transgenic Notch reporter mouse to examine whether the marrrow hematopoietic stem and myeloid progenitor cells have suppressed Notch signal transduction as a consequence of fucosylation deficiency. She will then determine if fucosylation-deficient hematopoietic progenitor cells display altered interactions with the marrow stromal environment. She will further examine the role of O-fucosylation in modifying Notch signaling in granulopoiesis by using mice deficient in the expression of pofut! that mediates the fucosylation of Notch EGF repeats, and by studying the pofutl-/- ES cell in vitro hematopoiesis. Finally, she will examine specifically which O-fucose residue on Notch! EGF repeats is important for Notch to exert its effect in granulopoietic regulation. This will be the first study to define the signaling transduction pathways controlling myelopoiesis that are activated in bone marrow stem and progenitor cells after engagement of fucosylated glycoprotein, such as Notch, with bone marrow microenviroment, and the mechanisms that ultimately contribute to the regulation of granulopoiesis. The outcome of these studies will provide insights as to whether dysregulated Notch signaling consequent to deficiency of O-fucosylation could play a role in human chronic myeloproliferative diseases. Resutls from the proposal will provide the basis for future studies to explore the significance of fucosylated glycoproteins including Notch and Notch ligands, and, perhaps other secreted or membrane associated fucosylated glycans, in hematopoietic stem cell self-renewal, myeloid fate specification and determination, and bone marrow niche competency in supproting hematopoietic stem cell activity.

描述（由申请人提供）：本赠款申请的总体目标是支持K08职业发展奖，该奖项着重于研究构造依赖性凹槽信号传导途径在调节髓样命运规格和髓样谱系发展中的作用。岩藻糖基化的聚糖与许多两种双重过程有关。在各种类型的细胞命运规范中，需要进行Notch细胞外EGF重复序列上的O连锁岩藻糖部分。该提案的主要研究者Lan Zhou在她与John Lowe博士的先前工作中以及在Case Western Reserve University进行的研究中确定了FX - / - 小鼠中的髓增生增生性表型，该表型有条件地缺乏细胞葡萄糖基化的缺陷，这是对Notch依赖于Notch依赖于Notch依赖性信号转移型肌动型型细胞的损失。在此提案中，周博士将使用转基因Notch Reporter小鼠检查骨髓造血干和髓样祖细胞是否抑制了由于岩藻糖基化缺陷而抑制了Notch信号转导。然后，她将确定缺陷型造血祖细胞是否显示出与骨髓基质环境的相互作用改变。她将进一步研究O羟基化在修饰粒状液体中Notch信号传导中的作用，通过使用缺乏Pofut表达的小鼠！这介导了Notch EGF重复的岩藻糖基化，并通过研究pofutl - / - ES细胞在体外造血中。最后，她将专门研究Notch上哪种O型糖糖残留物！ EGF重复量对于Notch在颗粒调节中发挥作用很重要。这将是第一个定义控制骨髓茎和祖细胞在构造糖基化糖蛋白接合后在骨髓茎和祖细胞中激活的信号转导途径的研究，例如Notch，具有骨髓微型微蛋白质，以及最终有助于颗粒颗粒的调节机制。这些研究的结果将提供有关O-凝血素化缺乏导致失调的缺口信号传导是否可以在人类慢性骨髓增生性疾病中发挥作用的见解。 Resutls from the proposal will provide the basis for future studies to explore the significance of fucosylated glycoproteins including Notch and Notch ligands, and, perhaps other secreted or membrane associated fucosylated glycans, in hematopoietic stem cell self-renewal, myeloid fate specification and determination, and bone marrow niche competency in supproting hematopoietic stem cell activity.