Red Cell Membrane Studies

总体项目摘要 贫血是影响全世界数百万人的主要健康问题。整体 该计划的目标是提高对以下问题的机械理解： 红细胞生成，目的是定义由于以下原因导致贫血的病理生理机制： 无效的红细胞生成。我们的首要假设是正常的人类红细胞生成需要 基因表达模式的重大变化，影响关键的相互联系的途径， 有丝分裂/胞质分裂、凋亡、代谢物转运和核结构。这些比较 将在许多重要的红细胞疾病中进行。四个独立的， 相互依赖的互补项目已经组装，以探索不同的方面， 人类红细胞生成。项目1将全面了解 在产生不同的红系细胞群体中基因表达的变化，特别关注 调节红系祖细胞和终末红系分化的晚期阶段，包括 正常和异常红细胞生成中的去核。项目2将开发一种机械 了解不同蛋白质的有序合成如何在红细胞生成过程中受到调节， 鉴定和表征调节基因表达的阶段特异性程序的增强子， 高度特化的人类红细胞与此同时，蛋白质在不同的时间进行mRNA翻译， 红细胞发育和分化的阶段将通过核糖体蛋白来定义和表征。 侧写项目3将发展对红系细胞代谢作用的机制性理解， 分化细胞因子在红系分化中的作用已被广泛研究，但其在红系分化中的作用仍有待进一步研究。 直到最近，我们才开始认识到营养物质进入和代谢的重要性， 过渡到不同的红细胞阶段，拟议的项目将使用一种新的配体支架， 代谢物转运蛋白，以扩大我们的基础知识代谢红细胞 分化这些数据将揭示代谢物调节红系细胞谱系的新途径 分化，并将导致识别和潜在的操纵营养转运蛋白， 定向红系祖细胞存活和分化的生理红细胞生成以及在 红细胞生成障碍项目4将发展对细胞作用的机械理解， 核硬度和极化收缩力在去核、骨髓排出和“自我”识别中的作用 由红系细胞的巨噬细胞。核纤层蛋白是细胞中主要的核结构蛋白， 调节核刚性和肌球蛋白驱动的细胞极化在这些过程中将被探讨。 这些见解将导致改善机制的理解关键细胞事件在红细胞 分化

Overall Project Abstract Anemia is a major health problem affecting millions of individuals around the world. The overall objective of the proposed program is to develop an improved mechanistic understanding of erythropoiesis, with the goal of defining pathophysiological mechanisms resulting in anemia due to ineffective erythropoiesis. Our overarching hypothesis is that normal human erythropoiesis requires major changes in patterns of gene expression that impact key interconnected pathways in mitosis/cytokinesis, apoptosis, metabolite transport and nuclear structure. Comparisons of these pathways will be performed in a number of important red cell disorders. Four independent but complementary projects that rely on each other have been assembled to explore different aspects of human erythropoiesis. Project 1 will develop a comprehensive mechanistic understanding of the role of changes in gene expression in generating distinct erythroid populations with particular focus on the regulation of erythroid progenitors and late stages of terminal erythroid differentiation including enucleation in normal and disordered erythropoiesis. Project 2 will develop a mechanistic understanding of how the ordered synthesis of distinct proteins is regulated during erythropoiesis by identifying and characterizing enhancers regulating stage-specific programs of gene expression in highly specialized human erythroid cells. In parallel, proteins undergoing mRNA translation at different stages of erythroid development and differentiation will be defined and characterized by ribosomal profiling. Project 3 will develop a mechanistic understanding of the role of cell metabolism in erythroid differentiation. The role of cytokines in erythroid differentiation has been extensively studied but it is only recently that we have begun to recognize the importance of nutrient entry and metabolism in transitioning to different erythroid stages and the proposed project will use a novel scaffold of ligands to metabolite transporters in order to extend our fundamental knowledge of metabolism in erythroid differentiation. These data will reveal novel pathways by which metabolites regulate erythroid lineage differentiation and will result in the identification, and potential manipulation of nutrient transporters that orient erythroid progenitor survival and differentiation in physiological erythropoiesis as well as in the disordered erythropoiesis. Project 4 will develop mechanistic understanding of the role of cell and nuclear stiffness and polarized contractile forces in enucleation, marrow egress, and `self' recognition by macrophages of erythroid cells. The role of lamins, the main nuclear structural proteins in cells, in regulating nuclear rigidity and of myosin-driven cell polarization in these processes will be explored. These insights will result in improved mechanistic understanding of key cellular event during erythroid differentiation.