Model to study the effects of ethanol on erythropoiesis

描述(从申请人的描述中扫描)：长期摄入 乙醇被提出用来加速发展和增加严重程度 在人类患者中引起巨幼细胞性贫血以及在患者中引起贫血 叶酸状态正常。提出的红细胞异常的机制 酒精中毒患者包括促红细胞生成素(EPO)产生的减弱 乙醇，降低红系前体细胞对EPO的敏感性 乙醇对红系祖细胞的毒性作用及抗叶酸活性 乙醇。各自在红系异常原因中的作用 与酒精中毒有关的研究尚未同时进行。在相同的 模型系统，因此还不清楚哪种可能的机制是 生理上最重要的。小鼠慢性酒精摄取模型的建立 将被开发，以确定其中每一个的意义 潜在机制，并进一步允许调查这一角色 性别在血液学异常的发生中的作用 慢性酒精摄入。乙醇对红系细胞的直接毒性作用 祖细胞将通过列举早期红系祖细胞来确定 乙醇灌胃和对照组小鼠，通过测定乙醇灌胃和灌胃的能力 对照组小鼠从急性贫血中恢复，并通过培养红细胞 从灌胃和对照小鼠不同浓度的乙醇中分离得到 用乙醇来确定乙醇对细胞的活力和程度的影响 红细胞的终末分化。EPO的生产将在#年进行评估 贫乏的乙醇喂养小鼠和对照小鼠。将确定乙醇是否 加重或加速叶酸缺乏的血液学症状 用或不加酒精的叶酸缺乏饮食使小鼠 补充。将从叶酸缺乏的小鼠中分离出红细胞 叶酸缺乏饮食和叶酸缺乏饮食小鼠 添加了乙醇。红细胞经历终末期的能力 纠正叶酸缺乏症后的体外分化 或没有乙醇，以确定乙醇是否延迟或 抑制叶酸缺乏的恢复。这项研究的结果可能是 对贫血和相关疾病的治疗具有重要意义 酗酒者。可能需要更高水平的叶酸补充剂 如果发现酒精对酒精中毒患者有直接影响，则应对其进行初步治疗 或对红细胞叶酸代谢的残留影响。更改内的 叶酸的体内生物利用度可能表明，如果乙醇对 红细胞在体内比在体外更明显。其他形式的 叶酸的输送(非肠外给药与口服给药)以及避免服用具有 治疗酗酒者的抗叶酸活性(抗惊厥药物和某些 广谱抗生素)因此可能会被授权增加 叶酸的生物利用度。

DESCRIPTION (Scanned from the applicant's description): Chronic ingestion of ethanol has been proposed to hasten the development and increase the severity of megaloblastic anemia in human patients, as well as cause anemia in patients with normal folate status. Proposed mechanisms for red cell abnormalities in alcoholic patients include attenuation of erythropoietin (EPO) production by ethanol, decreased sensitivity of erythroid precursor cells to EPO, direct toxic effects of ethanol on erythroid progenitors, and an antifolate activity of ethanol. The contributions of each in the cause of the erythroid abnormities associated with alcoholism have not been studied simultaneously. In the same model system and it is therefore unclear which of the potential mechanisms is physiologically greatest importance. A mouse model of chronic ethanol ingestion will be developed in order to determine the significance of each of these potential mechanisms, and further, to allow for the investigation of the role of gender in the development of hematologic abnormalities associated with chronic ethanol ingestion. Direct toxic effects of ethanol on erythroid progenitors will be determined by enumerating early erythroid progenitors in ethanol fed and control mice, by measuring the ability of ethanol fed and control mice to recover from acute anemia and by culturing erythroblasts isolated from ethanol fed and control mice in different concentrations of ethanol to determine the effect of ethanol on the viability and extent of terminal differentiation of erythroblasts. EPO production will be assessed in anemic ethanol fed and control mice. It will be determined if ethanol exacerbates or accelerates the hematologic symptoms of folate deficiency by subjecting mice to folate deficient diets with or without ethanol supplementation. Erythroblasts will be isolated from folate deficient mice on the folate deficient diet and from mice on the folate deficient diet supplemented with ethanol. The ability of erythroblasts to undergo terminal differentiation in vitro after correcting the folate deficiency in the presence or absence of ethanol will be investigated to determine if ethanol delays or inhibits the recovery form folate deficiency. The results of this study may be significant for the treatment of anemias and associated illnesses in alcoholics. Higher levels of folate supplementation may be required in the initial treatment of alcoholic patients if it is found that ethanol has direct or residual effects on folate metabolism in erythroblasts. Alteration of the in vivo bioavailablity of folate may be indicated if the effects of ethanol on erythroblasts are more pronounced in vivo than in vitro. Alternative forms of delivery of folate (parenteral vs oral) and the avoidance of drugs that have anti-folate activity for treatment of alcoholics (anticonvulsives and certain broad spectrum antibiotics) might thus be warranted order to increase the bioavailabilty of administered folate.