BIOLOGY AND FUNCTION OF CD44 ISOFORMS

CD44 是透明质酸 (HA) 的主要细胞表面受体，透明质酸是一种 普遍存在的 ECM 多糖深刻影响基质和 浸润细胞行为并在维持 组织稳态。 细胞周期期间 HA 积累增加 炎症、组织重塑和再生等增殖， 恶性肿瘤的发展和侵袭。 CD44-HA相互作用是 因此据信可调节多种细胞反应 体内肿瘤形成，这种效应是 CD44-HA 相互作用 依赖。 申请人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，并且具有 研究表明，糖基化提供了一种有效的调节机制 CD44-HA 相互作用，影响 CD44 的标准形式 (CD44H) 和编码膜片段的差异剪接外显子 近端域。 申请人将确定以下机制： 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 扩展这些实验来检查破坏肿瘤细胞的效果 使用可溶性重组 CD44 和抗 CD44 进行 CD44-ECM HA 相互作用 抗体。 具体来说，申请人将阐述 CD44 在 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，申请人开发出了一种转基因 皮肤中具有组织特异性 CD44 缺陷的小鼠模型。 该模型的可用性将提供解决以下问题的可能性： CD44在HA代谢、组织调节中的生理功能 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.