REGULATION OF PROTEIN SYNTHESIS AND ERYTHROPOIESIS

描述：（改编自研究者摘要）总体目的 这项建议的目的是更清楚地定义血红蛋白的调节， 在正常和异常血液学条件下的合成和红细胞生成。 特别是血红素调节的翻译抑制剂（HRI） 对未成熟红系细胞，尤其是网织红细胞中蛋白质合成的影响， 并研究血红素对HRI的调节作用。 HRI是血红素调节的 磷酸化真核生物α亚单位的蛋白激酶 起始因子2（eIF-2-α）。 α亚基的磷酸化 的eIF-2实质上抑制翻译起始的再循环 从而导致蛋白质合成的停止。 这项建议 因此，试图通过研究HRI的生理功能， 这种表达的消融或其活性的后果， 细胞培养和转基因动物。 三个具体目标是：1） 研究血红蛋白合成和晚红细胞的调节 HRI在小鼠红白血病细胞中的分化; 2）研究HRI在小鼠红白血病细胞中的作用 HRI在调节红系分化和HRI在 骨中红细胞分化和血红蛋白合成的调节 骨髓干细胞在培养和整个动物;和3）研究 胚胎发育过程中红系细胞的发育和血红蛋白的合成 在成年小鼠中通过敲除HRI基因。

DESCRIPTION: (Adapted from investigator's abstract) The overall objective of this proposal is to more clearly define the regulation of hemoglobin synthesis and erythropoiesis in normal and abnormal hematologic conditions. In particular, the role of the heme-regulated translational inhibitor (HRI) on protein synthesis in immature erythroid cells, especially reticulocytes, and the regulation of HRI by heme will be studied. HRI is a heme regulated protein kinase that phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF-2-alpha). The phosphorylation of the alpha subunit of eIF-2 substantially inhibits the recycling of translational initiation and thereby results in the cessation of protein synthesis. This proposal therefore seeks to clarify the physiologic function of HRI by studying the consequences of the ablation of this expression or in its activity both in cell culture and in transgenic animals. Three specific aims are listed: 1) to study the regulation of hemoglobin synthesis and late erythroid differentiation by HRI in murine erythroleukemia cells; 2) to study the role of HRI in the regulation of erythroid differentiation and HRI in the regulation of erythroid differentiation and hemoglobin synthesis in bone marrow stem cells in culture and in whole animals; and 3) to study the erythroid development and hemoglobin synthesis during embryonic development in adult mice by knock-out of the HRI gene.