GENE REGULATION IN LYMPHOHEMATOPOIETIC STROMAL CELLS

这一提议是基于这样一个前提，即一个共同的、多功能的 祖细胞分化为脂肪细胞、成骨细胞和淋巴管细胞。 骨髓微环境中的造血支持细胞。它是 旨在测试一些相互关联的假设，涉及 大鼠骨髓基质细胞分化和功能的调控 体外和体内。四个具体目标直接聚焦于这些问题：(1) 确定单抗是否针对克隆的 基质细胞系可以用来定义不同的亚群 流式细胞仪检测原代来源的基质细胞。(2)看是否 不同的细胞因子基因“超家族”调节基质细胞功能 一种常见的方式。(3)比较两组大鼠淋巴造血功能。 体外培养形态不同的基质细胞亚群。(4)至 测定细胞因子相对于基质的体内表达动力学 血液应激或成骨诱导后的细胞分化。 这些研究将检验基质细胞的相互依赖性。 脂肪生成、成骨和淋巴-造血，并确定 这些功能是相互排斥的。归根结底，这个目标是 该项目是开发一个描述细胞因子的综合模型 决定骨髓基质细胞生理学的机制。这些 这些发现将直接应用于反映间质的疾病状态 细胞调节失调，包括骨髓纤维化、骨质疏松症和继发性 溶骨性或骨硬化性肿瘤引起的骨转移。此外，他们还 可能会解决与其他组织中基质细胞稳态有关的问题 纸巾。随着临床医生越来越多地使用细胞因子治疗慢性粒细胞白血病 淋巴造血性疾病：改善对基质细胞的理解 对这些代理人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.