GLYCOLIPID MICRODOMAINS IN TUMOR CELL ADHESION /SIGNALIN

肿瘤细胞粘附/信号蛋白中的糖脂微域

• 批准号: 6633335
• 负责人: Sen-itiroh Hakomori
• 金额: $ 31.48万
• 依托单位: PACIFIC NORTHWEST RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6633335
• 关键词: antineoplastics; biological signal transduction; cell adhesion; cell line; chemical structure function; detergents; drug design /synthesis /production; glycosphingolipids; immunoprecipitation; lipid bilayer membrane; membrane structure; neoplastic cell; photoactivation; western blottings

DESCRIPTION (Adapted from applicant's abstract): Preliminary studies indicate that tumor-associated glycosphingolipid (GSL) antigens are clustered and organized with various signal transducer molecules (e.g. c-Src, Ras, FAK, Rho, Cak)as microdomains at the tumor cell surface membrane, termed ÒGSL-enriched microdomains (GEM). GSLs in GEM are involved in cell adhesion or stimulation by antibody, which initiate signal transduction. Thus, tumor-associated GSLs in GEM may play an essential role in defining aberrant adhesion and aberrant signal transduction characteristic of malignant tumor cells. The applicant proposes to study: (1) Organizational status and composition of GEM displaying GSL-dependent cell adhesion coupled with signaling. This includes isolation GEM subfraction, analysis of its chemical composition, association of GSLs with signal transducers, and the role of trans-bilayer lipophilic proteins present in GEM. (2) Functional analysis of GEM and its subfractions, defining GSL-dependent initiation and activation of signaling. This includes observation of activation or inhibition of transducers in whole cells or in subdomain vesicles following stimulation of GSLs. (3) Differences of structure and function of GEM in tumor cells with different grade of malignancy and state of differentiation. (4) Development of reagents which disrupt GSL clustering (uncouplers or inhibit GSL binding to its ligand (anti-ligands), and application of these reagents to disrupt GEM structure and function and thereby inhibit tumor growth and malignancy.

描述（改编自申请人的摘要）：初步研究表明 肿瘤相关的糖磷脂（GSL）抗原是聚集的，并且 用各种信号传感器分子组织（例如C-SRC，Ras，Fak，Rho，Rho， CAK）作为肿瘤细胞表面膜的微域，称为 r富集的微域（GEM）。宝石中的GSL参与细胞 抗体的粘附或刺激，启动信号转导。因此， GEM中与肿瘤相关的GSL可能在定义异常方面起重要作用 恶性肿瘤的粘附和异常信号转导特征 细胞。申请人建议研究：（1）组织状况和 显示GSL依赖性细胞粘附的宝石的组成与 信号。这包括隔离宝石亚折叠，对其化学的分析 组成，GSL与信号传感器的关联以及 GEM中存在的反式双脂亲脂蛋白。 （2）功能分析 宝石及其亚元素，定义了GSL依赖性的启动和激活 信号。这包括观察激活或抑制传感器 在刺激GSL之后，在全细胞或亚域囊泡中。 （3） 肿瘤细胞中宝石的结构和功能差异不同 恶性和分化状态等级。 （4）试剂的开发 哪些破坏GSL聚类（解耦合或抑制GSL与其配体结合 （反配体），以及这些试剂在破坏宝石结构和 功能，从而抑制肿瘤的生长和恶性肿瘤。