REGULATION OF PROTEIN SYNTHESIS AND ERYTHROPOIESIS

描述：(改编自调查员摘要)总体目标 这项建议的目的是更明确地定义血红蛋白的调节 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物(HRI)的作用 未成熟的红系细胞，特别是网织红细胞的蛋白质合成， 此外，还将研究血红素对HRI的调节。HRI是一种受管制的血红素 真核生物α亚基磷酸化的蛋白激酶 启动因子2(eIF-2-α)。α亚基的磷酸化 EIF-2的表达显著抑制了翻译起始的循环 从而导致蛋白质合成的停止。这项建议 因此，试图通过对HRI的研究来阐明HRI的生理功能 这一表达的消融或其活动的后果在 在细胞培养和转基因动物中。列出了三个具体目标：1) 晚期红系与血红蛋白合成调节的研究 HRI对小鼠红白血病细胞的诱导分化；2)研究其作用 HRI在调节红系分化中的作用及HRI的研究进展 骨中红系分化和血红蛋白合成的调节 在培养和整个动物中的骨髓干细胞；以及3)研究 胚胎发育过程中的红系发育和血红蛋白合成 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.