BONE MARROW CELL ADHESION MOLECULES

骨髓细胞粘附分子

• 批准号: 2068069
• 负责人: Paul Wayne Kincade
• 金额: $ 31.53万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-01 至 1997-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2068069
• 关键词: CD antigens; biological signal transduction; bone marrow; cell adhesion molecules; hamsters; hematopoiesis; hyaluronate; laboratory mouse; laboratory rat; molecular cloning; monoclonal antibody; protein structure function; site directed mutagenesis; tissue /cell culture

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.

长期骨髓培养、单抗和分子 克隆技术将被用于研究细胞黏附分子(CAM) 在骨髓和其他淋巴造血组织中表达。 CAM对于维持成熟血细胞之间的接触可能很重要 产生调节性的微环境的祖细胞和细胞 细胞因子。细胞在骨髓内的运动和它们在 成熟度可能取决于CAM调制和其中的缺陷 这一过程可能解释了疾病中细胞的异常迁移。它是 也可能是细胞-细胞和细胞-基质的受体。 骨髓内的沟通。然而，这些都不依赖于CAM 机制是很好理解的。抗CD44、VLA4和 VCAM-1被发现扰乱髓系和/或B系的产生 长期骨髓培养中的淋巴样细胞，这些分子将 在拟议的研究中得到特别强调。CD44分子打开 一些细胞，而不是其他细胞，识别透明质酸(HA)是一种粘连 莱兰德。这可能部分是由于CD44分子的复杂性造成的 蛋白异构体与PAN中活性亲和力的调节 CD44为HA。CD44的胞质结构域是重要的，而 细胞内和细胞外序列的贡献将是 是由突变决定的。某些抗CD44的单抗可阻断 HA识别，而其他人则显著增强了这一功能，可能是通过 诱导构象变化。识别的表位的位置 这些抗体将被确定。更多信息将是 了解这些凸轮在体内的分布和功能，以及 在胚胎发育过程中。这一假设将得到检验，即凸轮起中介作用。 骨髓细胞的跨膜信号转导，产生细胞因子 合成和分化事件。最后，同样的方法将 展开以确定细胞表达和使用哪些其他CAM 在骨髓中。这些研究将为我们提供信息。基础版 用于血细胞形成和发展的机制 免疫系统。其中一些发现也可能对 恶性肿瘤和其他疾病的诊断和治疗。