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: 2893218
• 负责人: Sen-itiroh Hakomori
• 金额: $ 24.86万
• 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 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2893218
• 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（改编自申请人摘要）：初步研究表明， 肿瘤相关鞘糖脂（GSL）抗原成簇， 与各种信号转导分子（例如c-Src，Ras，FAK，Rho， Cak）作为肿瘤细胞表面膜上的微区，称为 ÒGSL富集微区（GEM）。GEM中的GSL参与了细胞内 粘附或抗体刺激，启动信号转导。因此，在本发明中， GEM中的肿瘤相关GSL可能在确定异常GSL中起重要作用。 恶性肿瘤细胞粘附与异常信号转导特征 细胞申请人拟研究：（1）组织状况和 显示GSL依赖性细胞粘附的GEM组合物， 信号这包括分离GEM亚组分，分析其化学成分， GSL的组成、与信号转导的关联以及 存在于GEM中的跨双层亲脂蛋白。(2)的功能分析 GEM及其亚组分，定义GSL依赖性启动和激活 信号这包括观察传感器的激活或抑制 在GSL刺激后的全细胞或亚结构域囊泡中。（三） 不同肿瘤细胞中GEM结构和功能的差异 恶性程度和分化状态。(4)试剂开发 其破坏GSL成簇（解偶联剂或抑制GSL与其配体结合 （抗配体），以及这些试剂用于破坏GEM结构和 功能，从而抑制肿瘤生长和恶性。