BIOLOGY AND FUNCTION OF CD44 ISOFORMS

CD44是透明质酸(HA)的主要细胞表面受体， 无处不在的ECM多糖，深刻影响基质和 浸润性细胞行为，并在维持 组织动态平衡。在细胞周期中，HA的积累增加 炎症、组织重塑和再生中的增殖， 恶性肿瘤的发展和侵袭。CD44-HA相互作用是 因此被认为调节多种细胞反应的结果是 体内肿瘤形成及其与CD44-HA的相互作用 依附的。申请人已经观察到细胞内的表达 CD44结构域是肿瘤细胞在HA上迁移所必需的 研究表明，糖基化提供了一个有效的调节机制 CD44-HA相互作用，影响CD44标准型(CD44H) 以及编码一段膜的差异剪接外显子 近端区域。申请者将通过哪些机制来确定 糖基化调节CD44-HA相互作用并识别特异性 增强或抑制结合的碳水化合物基团。研究将会 扩大这些实验以检验破坏肿瘤细胞的效果 可溶性重组CD44和抗CD44与CD44-ECM HA的相互作用 抗体。具体地说，申请者将阐述CD44在 肿瘤细胞与宿主组织内皮和间质的黏附 肿瘤血管生成。最后，申请者开发出了一种转基因 皮肤中存在组织特异性CD44缺陷的小鼠模型。 此模型的推出将为解决 CD44在透明质酸代谢、组织调节中的生理作用 动态平衡、炎症和肿瘤发生。

CD44 is the principal cell surface receptor for hyaluronic acid (HA), a ubiquitous ECM polysaccharide which profoundly influences stromal and infiltrating cell behavior and plays a major role in the maintenance of tissue homeostasis. HA accumulation is increased during periods of cell proliferation as in inflammation, tissue remodeling and regeneration, development and invasion by malignancy. CD44-HA interaction is therefore believed to regulate multiple cellular responses as a results of tumor formation in vivo and that this effect is CD44-HA interaction dependent. The applicant has observed expression of the intracellular domain of CD44 is required for tumor cell migration on HA and have shown that glycosylation provides a potent regulatory mechanism for CD44-HA interaction, affecting both the standard form of CD44 (CD44H) and differentially spliced exons encoding a segment of the membrane proximal domain. The applicant will determine the mechanisms by which glycosylation regulates CD44-HA interaction and identify specific carbohydrate groups which enhance or inhibit binding. Studies will extend these experiments to examine the effects of disrupting tumor cell CD44-ECM HA interaction using soluble recombinant CD44 and anti CD44 antibodies. Specifically, the applicant will address the role of CD44 in tumor cell adhesion to host tissue endothelium and stroma as well as in tumor angiogenesis. Finally, the applicant has developed a transgenic mouse model which has tissue specific CD44 deficiency in the skin. Availability of this model will provide the possibility to address the physiologic function of CD44 in HA metabolism, regulation of tissue homeostasis, inflammation and tumorigenesis.