INVESTIGATING A ROLE FOR NOTCH SIGNALING IN ANGIOGENESIS

研究Notch信号传导在血管生成中的作用

• 批准号: 6173870
• 负责人: GERALDINE A WEINMASTER
• 金额: $ 13.99万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6173870
• 关键词: angiogenesis; biological signal transduction; cell migration; cell proliferation; cell type; chick embryo; chorioallantoic membrane; gene expression; ligands; membrane proteins; protein structure function; smooth muscle

Notch signaling has been implicated in a wide variety of processes from cell fate decisions, tissue patterning and morphogenesis to human disease. In fact, three of the four mammalian Notch genes are associated with cancer while the genes encoding Notch3 and the Notch ligand, Jagged1, are mutated in two inherited human diseases that involve defects in vascular development and maintenance. Furthermore, a role for Jagged1 in angiogenesis is emerging from our studies with mice deficient in Jagged1 that die early during embryogenesis, exhibiting defects in angiogenic remodeling. Interestingly, animals lacking the Notch ligand Delta1 also display a severe hemorrhagic phenotype. Taken together, these data strongly suggest a role for Notch signaling in angiogenesis. To investigate a role for Notch signaling in vascular development we will use the chick embryo chorioallantoic membrane (CAM). Our strategy is to introduce forms of Notch1 or its ligands, Delta1 and Jagged1 into the CAM, using retroviral-mediated expression, that will either activate or inhibit Notch signaling during vascularization of this membrane. Analysis of the effects produced through loss or gain in Notch activity will allow us to determine a role for Notch signaling in angiogenesis. Consistent with a role for Notch signaling during vascularization of the CAM, we have detected the expression of Notch1, Notch2, Jagged1 and Delta1 during development of this membrane and we are currently determining the CAM cell types that express these genes.

Notch信号转导已经涉及从细胞命运决定、组织图案化和形态发生到人类疾病的各种各样的过程。 事实上，四种哺乳动物Notch基因中的三种与癌症相关，而编码Notch 3和Notch配体Jagged 1的基因在两种涉及血管发育和维持缺陷的遗传性人类疾病中发生突变。 此外，从我们对缺乏Jagged1的小鼠的研究中发现，Jagged1在血管生成中的作用，这些小鼠在胚胎发育过程中早期死亡，表现出血管生成重塑的缺陷。 有趣的是，缺乏Notch配体Delta1的动物也表现出严重的出血表型。总之，这些数据强烈表明Notch信号传导在血管生成中的作用。 为了研究Notch信号传导在血管发育中的作用，我们将使用鸡胚绒毛尿囊膜（CAM）。 我们的策略是使用逆转录病毒介导的表达将Notch 1或其配体Delta1和Jagged1的形式引入CAM中，这将在该膜的血管化过程中激活或抑制Notch信号传导。 通过Notch活性的丧失或获得产生的影响的分析将使我们能够确定Notch信号传导在血管生成中的作用。 与Notch信号在CAM血管化过程中的作用一致，我们已经检测到Notch1，Notch2，Jagged1和Delta1在该膜发育过程中的表达，我们目前正在确定表达这些基因的CAM细胞类型。