Project 5 Frascati-mediated Mitochondrial Metabolism, Barry Paw

项目 5 弗拉斯卡蒂介导的线粒体代谢，Barry Paw

• 批准号: 9924635
• 负责人: Yvette Y Yien
• 金额: $ 33.9万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9924635
• 关键词: Acute Erythroblastic Leukemia; Affect; Anabolism; Anemia; Biochemical; Bioinformatics; Biological Process; Candidate Disease Gene; Carrier Proteins; Cell Proliferation; Cells; Child; Defect; Destinations; Development; Developmental Biology; Disease; Endosomes; Epitopes; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Exercise; Friends; Gene Expression Profiling; Genes; Genetic; Goals; Heme; Heme Iron; Hemoglobin; Human; Human Biology; Integral Membrane Protein; Iron; Iron Overload; Knowledge; Lead; Mammalian Cell; Mass Spectrum Analysis; Mediating; Metabolism; Mitochondria; Mus; Nutrient; Phenotype; Play; Pregnancy; Proteins; Proteome; Proteomics; Protoporphyrins; Role; Sorting - Cell Movement; Structural Genes; Structural Protein; Woman; Zebrafish; cofactor; extracellular; genetic approach; heme biosynthesis; insight; loss of function; mitochondrial metabolism; novel; protein complex; protein function; response; solute; tool; trafficking; transcriptome sequencing; Acute Erythroblastic Leukemia; Affect; Anabolism; Anemia; Biochemical; Bioinformatics; Biological Process; Candidate Disease Gene; Carrier Proteins; Cell Proliferation; Cells; Child; Defect; Destinations; Development; Developmental Biology; Disease; Endosomes; Epitopes; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Exercise; Friends; Gene Expression Profiling; Genes; Genetic; Goals; Heme; Heme Iron; Hemoglobin; Human; Human Biology; Integral Membrane Protein; Iron; Iron Overload; Knowledge; Lead; Mammalian Cell; Mass Spectrum Analysis; Mediating; Metabolism; Mitochondria; Mus; Nutrient; Phenotype; Play; Pregnancy; Proteins; Proteome; Proteomics; Protoporphyrins; Role; Sorting - Cell Movement; Structural Genes; Structural Protein; Woman; Zebrafish; cofactor; extracellular; genetic approach; heme biosynthesis; insight; loss of function; mitochondrial metabolism; novel; protein complex; protein function; response; solute; tool; trafficking; transcriptome sequencing

PROJECT SUMMARY The overall objective of this proposal is to identify and characterize novel proteins involved in erythroid iron/heme metabolism. Erythropoiesis is a massive exercise in cellular proliferation and synthesis of a single protein, hemoglobin. As a consequence, there is a tremendous demand for iron and heme to be efficiently trafficked within the developing erythron. Despite advances in our understanding of extra-cellular iron trafficking and proto-porphyrin biosynthesis, significant gaps remain, especially with respect to components involving the egress of iron from the endosomes to the mitochondria, the trafficking of iron/heme within the mitochondria, the transporters required for proto-porphyrin genesis, the cofactors that facilitate the intracellular trafficking of iron/heme, and the eventual export of heme from the mitochondria for its incorporation in hemoglobin. Using complementary approaches of genetics and bioinformatics from transcriptional profiling, we previously identified several proteins, such as Mitoferrin1 (Mfrn1), Sorting Nexin3 (Snx3), Tmem14c, Lat3, and Clpx1, as new components in the intracellular trafficking of iron, heme and nutrients crucial to red cell development. Although transcriptional profiling as provided insights, we showed that post-translational mechanisms play equally critical roles in the expression and function of proteins involved in iron and heme metabolism. Using quantitative mass spectrometry, we examined changes in the mitochondrial proteome as erythroid cells undergo maturation. We identified several solute carriers and transmembrane proteins, whose function in erythropoiesis have not been previously ascribed, that were induced with hemoglobinization. We propose to study the expression and loss-of-function phenotype of these 7 candidate genes (Aim 1). In particular, we plan to focus previously identified gene, Fam210b (c20orf108), and its interacting partners in red cell development (Aim 2). Functional elucidation of these structural genes will expand our knowledge into the unknown additional steps in intracellular solute, iron and heme trafficking crucial for erythropoiesis. The results of our proposal will provide us with new genetic tools to explore human disorders of anemias.

项目摘要 该建议的总体目的是识别和表征与红细胞相关的新型蛋白质 铁/血红素代谢。红细胞生成是一种在细胞增殖和合成中的大规模运动 蛋白质，血红蛋白。结果，对铁和血红素有巨大的需求有效 在发展中的Erythron中贩运。尽管我们对细胞外铁的理解取得了进步 贩运和原始孢子蛋白生物合成，仍然存在明显的差距，尤其是在组件方面 涉及铁从内体流出到线粒体，铁/血红素在 线粒体，原始卟啉创世纪所需的转运蛋白，辅助因子促进细胞内的辅助因子 铁/血红素的贩运，以及最终从线粒体中出口血红素，以融入 血红蛋白。使用转录分析的遗传学和生物信息学的互补方法，我们 以前已经确定了几种蛋白质，例如Mitoferrin1（MFRN1），分类Nexin3（SNX3），TMEM14C，LAT3和 Clpx1，作为铁，血红素和营养物质的细胞内运输中的新成分，对红细胞至关重要 发展。尽管所提供的见解，但我们表明了翻译后 机制在与铁和血红素有关的蛋白质的表达和功能中起着同样关键的作用 代谢。使用定量质谱法，我们检查了线粒体蛋白质组的变化 红细胞细胞经历成熟。我们确定了几个溶质载体和跨膜蛋白，它们的蛋白质 先前尚未归因于红细胞蛋白诱导的红细胞生成中的功能。我们 建议研究这7个候选基因的表达和功能丧失表型（AIM 1）。在 特别是，我们计划将以前确定的基因，FAM210B（C20ORF108）及其相互作用的伙伴以红色为重点 细胞开发（AIM 2）。这些结构基因的功能阐明将使我们的知识扩展到 细胞内溶质，铁和血红素运输的其他步骤对促红细胞生成至关重要。结果 我们的建议将为我们提供新的遗传工具来探索贫血的人类疾病。