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METABOLIC AND MOLECULAR CONTROL OF MYELOPOIESIS

骨髓细胞生成的代谢和分子控制

基本信息

批准号：
3458170
负责人：
ALAN MARSHALL MILLER
金额：
$ 8.97万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-07-01 至 1993-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3458170
关键词：
hematopoiesis leukopoiesis myelocyte myeloid stem cell

项目摘要

Continuous presence of a glycoprotein termed colony stimulating factor (CSF) is necessary for the in vitro clonal growth of the committed granulocyte-macrophage progenitor cell (CFU-GM). CSF stimulates the release of arachidonic acid from membrane phospholipids, and arachidonic acid is then transformed to products of cyclooxygenation and lipoxygenation. Inhibition of lipoxygenase and specifically of the synthesis of leukotrienes C and D (LTC and LTD) blocks CSF-induced colony growth, and the block can be partially reversed by addition of LTC or LTD. CFU-GM from a subset of patients with acute non-lymphoblastic leukemia (ANLL) exhibit resistance to the inhibitory effects of high concentrations of lipoxygenase inhibitors. This may reflect a release from a normal regulatory mechanism related to oncogenesis. The metabolism of lipoxygenase intermediates to LTC and LTD depends on glutathione reductase, glutathione S-transferase and gamma-glutamyl transpeptidase. The genes for two of these enzymes have been localized to chromosomes that are frequently involved in cytogenetic abnormalities associated with ANLL. The overall objective of the proposed research is to further elucidate the role of arachidonic acid and glutathione metabolism in normal CSF stimulated CFU-GM growth and in leukemia by 1) determining the role of specific critical enzymes of leukotriene and glutathione metabolism in normal and leukemic myeloid cell; and 2) examining changes in the activity of those specific enzymes as leukemic cell lines are induced to differentiate. To accomplish this, recombinant human CSF, semi-purified bone marrow progenitor cells from normal and leukemic individuals, and well- characterized human leukemic cell lines will be used. Enzymes in the lipoxygenase pathway will be inhibited selectively. Patterns of inhibition of the leukemic cell lines will be compared with normal and leukemic bone marrow cells. The content and activity of enzymes which are found to impact on normal and leukemic colony formation will be quantitated and related to growth patterns. The results of these studies will enhance our knowledge of normal and neoplastic regulation and will serve to focus future studies on the molecular genetics of altered regulation in leukemic cells.

一种称为集落刺激因子的糖蛋白的持续存在 (Csf)是体外克隆生长所必需的。粒细胞-巨噬细胞前体细胞(CFU-GM)。脑脊液刺激释放从膜磷脂中提取花生四烯酸，花生四烯酸是然后转化为环氧合和脂氧合的产物。抑制脂氧合酶，并特异性抑制其合成白三烯C和D(LTC和LTD)阻断脑脊液诱导的集落生长，以及通过添加LTC或LTD，可以部分反转该块。部分急性非淋巴细胞白血病患者的CFU-GM (ANLL)表现出对高浓度抑制作用的抗性脂肪氧合酶抑制剂。这可能反映了从正常情况下的释放与肿瘤发生相关的调控机制。脂氧合酶的代谢 LTC和LTD的中间体依赖于谷胱甘肽还原酶，谷胱甘肽 S转移酶和γ-谷氨酰转肽酶。其中两个的基因酶被定位在染色体上，这些染色体经常涉及到与ANLL相关的细胞遗传学异常。拟议研究的总体目标是进一步阐明花生四烯酸和谷胱甘肽代谢在正常脑脊液中的作用刺激CFU-GM的生长和在白血病中的作用白三烯和谷胱甘肽代谢的特异性关键酶正常和白血病髓系细胞；2)检测活性的变化当白血病细胞系被诱导为差异化。为了做到这一点，重组人脑脊液，半纯化的骨髓来自正常人和白血病患者的祖细胞，以及- 将使用具有特征性的人类白血病细胞系。细菌中的酶脂氧合酶途径将被选择性地抑制。抑制模式的白血病细胞株将与正常和白血病的骨骼进行比较骨髓细胞。被发现影响酶的含量和活性关于正常和白血病集落形成将被量化和关联增长模式。这些研究的结果将提高我们对正常和肿瘤调节，并将用于未来的研究重点白血病细胞调节改变的分子遗传学。