REGULATION OF MYELOID PROGENITOR CELL DIFFERENTIATION

本应用程序将研究 重组生长因子和抑制剂在控制骨髓 祖细胞增殖的相互理解 这些生物分子的作用对于最终的临床治疗是重要的。 利用这些因素进行生物治疗。 的相互调节作用 重组鼠和人生长因子G-CSF、GM-CSF、M-CSF （CSF 1）白细胞介素3和白细胞介素1，以及抑制剂、干扰素 α、β和γ肿瘤坏死因子（TNF）和前列腺素 E（PCE），用于控制小鼠和人类造血 将研究祖细胞增殖。 一种新颖的前列腺素E2 已证实诱导的造血抑制机制 完整的动物，具有广泛的影响，以抑制 再生障碍性贫血、慢性粒细胞缺乏性贫血 疾病和白血病。 生长因子能够类似地 诱导这种机制，或者保护和/或推翻这种机制 将在完整动物和体外细胞培养物中进行分析 一种来源于小鼠骨髓和脾脏的可溶性抑制剂 在体内用PGE 2处理的细胞将被生物化学纯化， 测序，克隆，并确定其作用机制。 的 PGE 2或介导其作用的纯化蛋白的能力， 在致死辐射的动物模型中， 和化疗，将在正常动物和肿瘤宿主中进行测试。 生长因子对提高生存率的作用将是 研究了 人类辅助细胞之间的关系 因子，特别是CSF、PGE、IFN和TNF， 来源、释放动力学和对红细胞生成的影响， 将使用纯化的辅助细胞在体外研究骨髓生成 群体，高富集祖细胞群体，重组 因子、PGE 2放射免疫测定和原位杂交 技术. 转化生长因子β对人类免疫功能的潜在调节作用 将使用体外克隆琼脂研究造血 方法.

This application will investigate the relationships between recombination growth factors and inhibitors in controlling myeloid progenitor cell proliferation the understanding of the interactive effects of these biomolecules is important to the ultimate clinical use of these factors for biotherapy. The interegulatory roles of recombinant murine and human growth factors G-CSF, GM-CSF, M-CSF (CSF1) Interleukin 3 and Interkeukin 1, and inhibitors, interferons alpha, beta and gamma Tumor Necrosis Factor (TNF) and prostaglandin E (PCE), in the control of murine and human hematopoietic progenitor cell proliferation will be investigated. A novel-PGE2 induced hematopoietic suppressor mechanism has been demonstrated intact animals which has broad implications to suppressed hematopoiesis in patients with Aplastic Anemia, Anemia of Chronic Disease, and Leukemia. The ability of growth factors to similarly induce such a mechanism, or protect and/or override this mechanism will be analyzed in intact animals and in in vitro cell cultures A soluble inhibitor derived from bone marrow and spleens of mice treated with PGE2 in vivo will be biochemically purified, sequenced, cloned, and its mechanism of action determined. The capacity of PGE2 or the purified protein which mediates its effect, to protect hematopoiesis, in animal models of lethal irradiation and chemotherapy, will be tested in normal animals and tumor hosts. The role of growth factors to potentiate survival will be investigated. The interrelationships between human accessory cell factors, notably CSFs, PGE, IFNs and TNF with respect to cell source, kinetics of release and effects upon Erythropoiesis and Myelopoiesis will be studied in vitro using purified accessory cell populations, high enriched progenitor cell populations, recombinant factors, radioimmunoassays for PGE2 and in situ hybridization techniques. The potential regulatory effects of TGF beta on human hematopoiesis will be investigated using in vitro clonal agar methods.