Regulation of an Angiogenic Phenotype by Jagged 1

Jagged 1 对血管生成表型的调节

• 批准号: 6536072
• 负责人: Deena J Small
• 金额: $ 3.05万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-24 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6536072
• 关键词: 3T3 cells; actin binding protein; actins; angiogenesis; angiogenesis factor; athymic mouse; collagen; gene deletion mutation; membrane proteins; mitogen activated protein kinase; phosphoproteins; protooncogene; reporter genes; secretory protein

DESCRIPTION (provided by applicant): Notch receptors and their ligands are evolutionarily conserved transmembrane polypeptides that regulate cell fate determination and are associated with physiological and pathological processes such as angiogenesis and tumorigenesis. In order to understand the role of Jagged 1/Notch signaling in these processes, the phenotype of NIH 3T3 cells stably transfected with a non-transmembrane and secreted form of human Jagged 1 (sJ1) found to be upregulated during angiogenesis was examined. sJ1 transfectants exhibit a transformed phenotype that includes changes in cell morphology, increased survival at clonal density, anchorage-independent growth in soft agar in the presence of FGF1 and alterations in migratory behavior. sJ1 cells are also able to elicit an angiogenic response in the chorioallantoic membrane assay (CAM) and implantation of sJ1 transfected cells into athymic mice yielded highly angiogenic masses. The mechanisms by which sJ1 induces these phenotypic changes are unknown and are addressed by the two specific aims of this proposal 1) to determine if the NIH 3T3 sJ1 phenotype results from activation or inhibition of specific Notch receptor signaling pathways and 2) to determine the minimal domain of sJ1 sufficient to induce the sJ1 phenotype in NIH 3T3 cells. These objectives will be met by characterizing NIH 3T3 cells stably transfected with J 1 and Notch deletion mutants using a novel biological assay based on the laboratory?s characterization of sJ1 transfectants. Elucidation of the mechanisms by which sJ1 regulates cellular phenotype may aid in the development of therapeutic agents used for the treatment of pathological conditions such as cancer.

描述（由申请人提供）：Notch受体及其配体是 调节细胞命运的进化保守的跨膜多肽 确定并与生理和病理过程有关 例如血管生成和肿瘤发生。为了了解 在这些过程中锯齿状的1/Notch信号传导，NIH 3T3细胞的表型 稳定地用非跨膜和分泌的人类锯齿状的分泌形式转染1 （SJ1）发现在血管生成过程中被发现上调。 SJ1 转染物表现出一种转化的表型，包括细胞的变化 形态学，克隆密度的生存率增加，独立于锚固的生长 在FGF1存在的软琼脂中，迁移行为的改变。 SJ1 细胞还能够在绒毛膜上引起血管生成反应 膜测定（CAM）和SJ1转染细胞植入到无胸腺 小鼠产生高度的血管生成肿块。 SJ1诱导的机制 这些表型变化尚不清楚，并由两个特定目的解决 该提案的1）确定NIH 3T3 SJ1表型是否是由 激活或抑制特定缺口受体信号通路和2） 确定足以诱导SJ1表型的SJ1的最小结构域 在NIH 3T3细胞中。这些目标将通过表征NIH 3T3细胞来实现 使用新型生物学的J 1和Notch缺失突变体稳定转染 基于SJ1转染剂的实验室表征的测定。 阐明SJ1调节细胞表型的机制可能有助于 在用于治疗病理治疗的治疗剂中 癌症等疾病。