BONE MARROW CELL ADHESION MOLECULES

长期骨髓培养，单克隆抗体和分子 克隆技术将用于研究细胞粘附分子（CAM） 在骨髓和其他淋巴造血组织中表达。 CAM可能对维持成熟血细胞之间的接触很重要， 微环境的祖细胞和细胞， 细胞因子 细胞在骨髓中的运动和它们的排出， 成熟度可能取决于CAM调制和缺陷， 这个过程可以解释疾病中细胞的异常迁移。 是 CAM也可能作为细胞-细胞和细胞-基质的受体 骨髓内的沟通。 然而，这些依赖CAM的 机制很好理解。 抗CD 44、VLA 4和 发现VCAM-1破坏髓系和/或B谱系的产生 长期骨髓培养物中的淋巴细胞，这些分子将 在拟议的研究中得到特别强调。 CD 44分子 一些细胞，而不是其他细胞，识别透明质酸盐（HA）作为粘附 配体。 这可能部分是由于CD 44的分子复杂性。 蛋白质异构体和泛从主动调节的亲和力， HA的CD 44。 CD 44的胞质结构域是重要的， 细胞内和细胞外序列的贡献将是 通过诱变确定。 某些抗CD 44单克隆抗体阻断 HA识别，而其他人显着增强这一功能，也许是通过 诱导构象变化。 识别的表位的位置 将测定这些抗体。 其他信息将 寻求这些CAM在体内的分布和功能， 在胚胎发育过程中。 将检验CAM介导 骨髓细胞中的跨膜信号传导，导致细胞因子 合成和分化事件。 最后，同样的方法将 以确定细胞表达和使用的其他CAM 在骨髓中。 这些研究将提供信息。基本 用于血细胞形成和发育的机制 免疫系统 一些发现也可能对 诊断和治疗恶性肿瘤和其他疾病。

Long term bone marrow cultures, monoclonal antibodies and molecular cloning techniques will be used to study cell adhesion molecules (CAMs) that are expressed in bone marrow and other lymphohemopoietic tissues. CAMs may be important for maintaining contact between maturing blood cell progenitors and cells of the microenvironment which produce regulatory cytokines. The movement of cells within marrow and their egress at maturity is probably dependent on CAM modulation and defects in this process could account for abnormal migration of cells in disease. It is also likely that CAMs act as receptors for cell - cell and cell - matrix communication within bone marrow. However, none of these CAM-dependent mechanisms are well understood. Monoclonal antibodies to CD44, VLA4 and VCAM-1 were found to disrupt production of myeloid and/or B lineage lymphoid cells in long term bone marrow cultures and these molecules will receive particular emphasis in the proposed studies. CD44 molecules on some cells, but not others, recognize hyaluronate (HA) as an adhesion ligand. This may result in part from molecular complexity of CD44 protein isoforms and in pan from active regulation of the affinity of CD44 for HA. The cytoplasmic domain of CD44 is important, and the contributions of intracellular and extracellular sequences will be determined by mutagenesis. Certain monoclonal antibodies to CD44 block HA recognition, whereas others markedly enhance this function, perhaps by inducing conformational changes. The position of epitopes recognized by these antibodies will be determined. Additional information will be sought about the distribution and function of these CAMs in vivo and during embryogenesis. The hypothesis will be tested that CAMs mediate transmembrane signaling in bone mar-row cells, resulting in cytokine synthesis and differentiation events. Finally, the same approaches will be expanded to determine what other CAMs are expressed and used by cells in bone marrow. These studies will be informative about. basic mechanisms utilized for blood cell formation and for development of the immune system. Some of the findings may also have implications for diagnosis and treatment of malignancies and other diseases.