GLYCOLIPID MICRODOMAINS IN TUMOR CELL ADHESION /SIGNALIN

描述(摘自申请者的摘要)：初步研究表明 肿瘤相关的鞘糖脂(GSL)抗原聚集并 由各种信号转导分子(例如，c-Src，RAS，FAK，Rho， CAK)作为肿瘤细胞表面膜上的微区，称为 &OGrave；GSL富含微域(GEM)。创业板中的GSLs参与细胞 抗体的黏附或刺激，启动信号转导。因此， GEM中肿瘤相关的GSLS可能在定义异常中起重要作用 恶性肿瘤的黏附和异常信号转导特征 细胞。申请人拟学习：(1)组织地位和 显示GSL依赖的细胞黏附偶联的GEM组合物 发信号。这包括分离宝石亚组分，分析其化学成分 GSLS的组成、与信号转导的联系以及GSLS的作用 宝石中存在的跨双层亲脂蛋白。(2)功能分析 GEM及其亚组分，定义GSL依赖的启动和激活 发信号。这包括观察传感器的激活或抑制 在刺激GSLS后，整个细胞或亚域的囊泡中。(3) 不同肿瘤细胞间GEM结构和功能的差异 恶性程度和分化状态。(4)试剂的发展 破坏GSL聚集(解偶联剂或抑制GSL与其配体的结合 (反配体)，以及这些试剂在破坏宝石结构和 功能，从而抑制肿瘤生长和恶性肿瘤。

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.