REGULATION OF NORMAL AND NEOPLASTIC HEMATOPOIETIC CELL GROWTH--ROLE OF BRMS

这个项目的目标是更好地了解细胞外和 细胞内正负调控因子之间的相互作用 造血干细胞(SC)与糖尿病发病机制的关系(S) 恶变及其对治疗发展的作用 基因治疗方案。启动和保持增长和 原始祖细胞的分化与多种细胞因子 刺激是必需的。这就产生了“事实上的增长”的概念 我们证明了这种协作性也发生在负向 调节造血细胞的生长，并认为原始的能力 祖细胞的增殖取决于正负平衡 细胞接收到的信号。在仅研究的几种抑制性细胞因子中 转化生长因子-β对所有造血干细胞的直接和可逆性抑制 具有骨髓再生能力的种群。转化生长因子-β具有抑制作用 多种细胞因子受体对细胞表面表达的影响 与其对细胞生长的影响直接相关。SC因子受体 (c-kit)的表达被转化生长因子-β下调的部分原因是通过影响c-kit。 KIT信使核糖核酸稳定性。转化生长因子-β对S期细胞周期的影响 通过调节c-蛋白的细胞内机制进行进展 MYB和c-myc。体内实验结果表明，转化生长因子-β可以 保护小鼠免受5-FU的致命性造血毒性 因为DXR的非造血毒性。研究结果表明， 造血负性调节剂可成功应用于全身 以调节体内的化学保护。几个积极的监管机构 在体内使用造血细胞来确定它们对 骨髓再生。重组人白介素7给药小鼠每日2次，连续7天 不会明显改变BM的细胞密度，但会导致3倍于 脾中白细胞总数增加5倍，最高可达 外周血白细胞总数增加20倍。使用我们的 调节血细胞生长的能力，我们确定了 在此条件下进行基因转移的可行性。我们确定了 体外将HS-tk自杀基因导入T细胞 输注造血干细胞可允许体内选择性耗竭 如果随后需要的话，可以用更昔洛韦(GCV)治疗这些T细胞。

The goal of this project is to better understand the extracellular and intracellular interactions between positive and negative regulators of hematopoietic stem cells (SC) as they pertain to the mechanism(s) of malignant transformation and to the development of therapeutically useful gen therapy protocols. To initiate and maintain the growth and differentiation of primitive progenitor cells, multiple cytokine stimulation is required. This has led to the concept of "growth facto synergy". We show that such cooperativity also occurs between negative regulators of hematopoietic cell growth, and that the ability of primitive progenitors to proliferate depends on the balance of positive and negative signals the cell receives. Of several inhibitory cytokines studied only TGF-beta directly and reversibly inhibited all hematopoietic SC populations with marrow repopulating ability. TGF-B has inhibitory effects on the cell surface expression of many cytokine receptors that directly correlates with its effect on cell growth. SC factor receptor (c-kit) expression is down-regulated by TGF-beta in part by affecting c- kit mRNA stability. Also, TGF-beta prevents S phase cell cycle progression through an intracellular mechanism involving regulation of c- myb as well as c-myc. In vivo results demonstrated that TGF-beta can protect mice from both the lethal hematopoietic toxicity of 5-FU, as well as the non-hematopoiesis toxicity of DXR. The findings show that a negative regulator of hematopoiesis can be successfully used systemically to mediate chemoprotection in vivo. Several positive regulators of hematopoietic cells were used in vivo to determine their effect on myelopoiesis. The administration of rhIL-7 to mice twice a da for 7 days does not appreciably change BM cellularity, but does result in a 3-fold to 5-fold increase in the total number of leukocytes in the spleen and up to a 20-fold increase in the total number of peripheral WBC. Using our ability to regulate the growth of hematologic cells, we determined the feasibility of gene transfer under these conditions. We established that the ex-vivo transfer of the HS-tk suicide gene into T-cells before their infusion with hematopoietic SC could allow for selective in vivo depletion of these T-cells with ganciclovir (GCV) if the need subsequently arises.