GENE REGULATION IN LYMPHOHEMATOPOIETIC STROMAL CELLS

这一建议的前提是，一个共同的，多功能的 祖细胞产生脂肪细胞、成骨细胞和淋巴细胞， 骨髓微环境的造血支持细胞。是 旨在测试一些相互关联的假设， 骨髓基质细胞分化和功能的调节 体外和体内。四个具体目标直接关注这些问题：（1） 为了确定是否有针对克隆的 基质细胞系可用于定义细胞内不同亚群 通过流式细胞术检测原代来源的基质细胞。(2)以查看是否 不同的细胞因子基因“超家族”调节间质细胞功能， 普通的方式。(3)比较两组患者的淋巴造血功能， 形态学上不同的基质细胞亚群。(4)到 测定细胞因子表达相对于基质细胞的体内动力学 在血液应激或成骨诱导后的细胞分化。 这些研究将检查基质细胞的相互依赖性， 脂肪生成、骨生成和淋巴造血，并确定 这些功能是相互排斥的。最终，这个项目的目标 项目是开发一个全面的模型，描述细胞因子 决定骨髓基质细胞生理学的机制。这些 研究结果将直接应用于反映基质 细胞失调，包括骨髓纤维化、骨质疏松症和继发性 溶骨性或骨肉瘤引起的骨转移。此外他们 可以解决与基质细胞稳态有关的问题， 组织中随着临床医生扩大使用细胞因子治疗 淋巴造血系统疾病，提高对基质细胞的认识 对这些药剂的反应将变得越来越重要。

This proposal is based on the premise that a common, multi-potent progenitor cell gives rise to the adipocytes, osteoblasts, and lympho- hematopoietic supporting cells of the bone marrow microenvironment. It is designed to test a number of inter-related hypotheses concerning the regulation of bone marrow stromal cell differentiation and function in vitro and in vivo. Four SPECIFIC AIMS focus directly on these issues: (1) To determine whether monoclonal antibodies directed against a cloned stromal cell line can be used to define distinct subpopulations within primary derived stromal cells by flow cytometry. (2) To see whether distinct cytokine gene "superfamilies" regulate stromal cell function in a common manner. (3) To compare the lymphohematopoietic function of morphologically distinct stromal cell sub populations in vitro. (4) To determine the in vivo kinetics of cytokine expression relative to stromal cell differentiation following hematologic stress or osteogenic induction. These studies will examine the inter-dependence of stromal cell adipogenesis, osteogenesis, and lympho-hematopoiesis and determine if these functions are mutually exclusive. Ultimately, the goal of this project is to develop a comprehensive model describing the cytokine mechanisms which determine bone marrow stromal cell physiology. These findings will have direct application to disease states reflecting stromal cell dysregulation, including myelofibrosis, osteoporosis, and secondary bone metastases by osteolytic or osteosclerotic tumors. In addition, they may address questions relating to stromal cell homeostasis in other tissues. As clinicians expand their use of cytokines in the treatment of lymphothematopoietic disorders, improved understanding of the stromal cell response to these agents will become of increasing importance.