BIOLOGY AND FUNCTION OF CD44 ISOFORMS

CD 44是透明质酸（HA）的主要细胞表面受体， 广泛存在的ECM多糖，其深刻影响基质和 浸润细胞的行为，并发挥了重要作用，在维护 组织内稳态 在细胞周期中HA积累增加 增殖如炎症、组织重塑和再生， 恶性肿瘤的发展和侵袭。 CD 44-HA相互作用是 因此被认为调节多种细胞反应， 体内肿瘤形成，这种作用是CD 44-HA相互作用 依赖。 申请人已经观察到细胞内 CD 44的结构域是肿瘤细胞在HA上迁移所必需的， 表明糖基化提供了一种有效的调节机制， CD 44-HA相互作用，影响CD 44的标准形式（CD 44 H） 和编码膜片段的差异剪接外显子 近端域 申请人将确定 糖基化调节CD 44-HA相互作用并鉴定特异性 增强或抑制结合的碳水化合物基团。 研究将 将这些实验扩展到研究破坏肿瘤细胞的效果， 使用可溶性重组CD 44和抗CD 44抗体的CD 44-ECM HA相互作用 抗体的 具体而言，申请人将阐述CD 44在以下方面的作用： 肿瘤细胞与宿主组织内皮和基质的粘附以及 肿瘤血管生成 最后，申请人开发了一种转基因的 皮肤中存在组织特异性CD 44缺陷的小鼠模型。 该模型的可用性将提供解决 CD 44在HA代谢中的生理功能， 稳态、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.