The Transport of Nutritional Heme in Animal Development

动物发育中营养血红素的运输

• 批准号: 8986541
• 负责人: Iqbal Hamza
• 金额: $ 52.27万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8986541
• 关键词: African; African American; Anemia; Animal Model; Animals; Apical; Bioavailable; Biochemical; Biological; Bone Marrow; Caenorhabditis elegans; Cells; Consumption; Cytoplasm; Development; Diet; Disease; Eating; Embryo; Enterocytes; Erythrocytes; Erythrophagocytosis; Exhibits; Frequencies; Functional disorder; Funding; Genes; Genetic; Goals; Grant; Heme; Heme Iron; Hemeproteins; Hemochromatosis; Hemoglobin; Hemorrhage; Homeostasis; Homologous Gene; Hookworms; Human; Individual; Infant; Intestines; Iron; Iron Metabolism Disorders; Iron Overload; Knowledge; Lead; Mammalian Cell; Mammals; Meat; Mediating; Membrane; Membrane Protein Traffic; Metabolism; Molecular; Molecular Mimicry; Mothers; Mus; Nematoda; Nutraceutical; Nutrition Disorders; Nutritional; Organoids; Parasites; Parasitic Diseases; Pathway interactions; Patients; Phagocytosis; Phagolysosome; Pharmaceutical Preparations; Phenocopy; Positioning Attribute; Process; Proteins; RNA Interference; Rattus; Recycling; Reticuloendothelial System; Role; Sorting - Cell Movement; Source; System; Technology; Testing; Variant; Yeasts; Zebrafish; attenuation; auxotrophy; base; cofactor; cohort; cytotoxic; design; genetic approach; heme a; human disease; in vivo; innovation; iron deficiency; iron metabolism; iron protoporphyrin IX; macrophage; nutrition; pregnant; protein complex; public health relevance; senescence; small hairpin RNA; tool; trafficking; western diet

 DESCRIPTION (provided by applicant): The long-term goals of this proposal are to define the cellular and molecular determinants of heme homeostasis in human nutrition. Heme is a significant source of bioavailable iron for enterocytes where heme-iron is absorbed and for macrophages where heme-iron is recycled. In the human intestine, dietary heme is more easily absorbed than inorganic iron and is the source for the majority of body iron from a western diet. Moreover, over 70% of the total body iron is present as heme in hemoglobin. Iron from heme is recycled by phagocytosis of senescent red blood cells in the phagolysosome of macrophages. As of yet, the genes and pathways responsible for heme transport in the human intestine and macrophages of the reticuloendothelial system remain poorly defined. As a hydrophobic and cytotoxic cofactor, heme must be transported in a highly controlled manner through membranes via specific intra- and inter-cellular pathways. Prior to the last funding period, the identity of ny heme importer was unknown. We established that the roundworm Caenorhabditis elegans is an excellent animal model to identify heme transport pathways because it synthesizes a large number of hemoproteins with human homologs but does not synthesize heme de novo. By exploiting the heme auxotrophy of C. elegans in the previous grant cycle, we successfully identified the first eukaryotic heme importer/transporter, HRG1, and its corresponding human homolog, a discovery which provided the first preliminary framework for heme transport and trafficking in animals. HRG1 is essential for macrophage iron homeostasis and transports heme from the phagolysosome to the cytoplasm during phagocytosis of senescent RBCs - a process called erythrophagocytosis (Cell Metabolism 2013). Importantly, our studies reveal that a HRG1 variant in humans is defective in heme transport. The studies in this proposal are designed to elucidate the precise mechanisms of heme transport by HRG1 at the molecular, cellular, and organismal levels. We seek to test the hypothesis that HRG1 is the elusive human intestinal heme transporter and part of an essential heme trafficking network. We will utilize (a) a cell biological approach to establish HRG1 as the intestinal heme transporter; (b) a genetic approach to elucidate the molecular consequence of HRG1 variants in human iron metabolism disorders; and (c) a biochemical approach to uncover additional upstream and downstream interactors of HRG1 comprising a functional heme trafficking network. Our goal is to obtain a comprehensive understanding of the pathways which mediate heme transport in mammals that have, heretofore, remained poorly understood.

 描述（由申请人提供）：该提案的长期目标是确定人类营养中血红素稳态的细胞和分子决定因素，血红素是吸收血红素铁的肠细胞和巨噬细胞的生物可利用铁的重要来源。血红素铁在人体肠道中被回收，膳食血红素比无机铁更容易被吸收，并且是西方饮食中大部分身体铁的来源。体内铁总量的 70% 以血红蛋白中的血红素形式存在，血红素中的铁通过巨噬细胞吞噬溶酶体中衰老红细胞的吞噬作用进行回收。迄今为止，负责人体肠道和巨噬细胞中血红素运输的基因和途径。作为一种疏水性和细胞毒性辅助因子，血红素必须通过特定的内膜以高度受控的方式转运。在上一个资助期之前，纽约血红素输入者的身份尚不清楚，我们确定线虫是识别血红素转运途径的绝佳动物模型，因为它合成大量与人类同源的血红素蛋白。但不从头合成血红素。通过利用秀丽隐杆线虫的血红素营养缺陷型，我们成功地鉴定了第一个真核血红素。 HRG1 及其相应的人类同源物，这一发现为动物血红素运输和贩运提供了第一个初步框架，对于巨噬细胞铁稳态至关重要，并在衰老红细胞的吞噬过程中将血红素从吞噬溶酶体运输到细胞质。一个称为噬红细胞作用的过程 (Cell Metabolism 2013) 重要的是，我们的研究表明 HRG1 变异存在于人类在血红素转运方面存在缺陷。本提案中的研究旨在从分子、细胞和生物学水平阐明 HRG1 血红素转运的精确机制。我们试图验证 HRG1 是难以捉摸的人类肠道血红素转运蛋白的假设。我们将利用（a）细胞生物学方法将HRG1建立为肠道血红素转运蛋白；（b）利用遗传方法阐明HRG1变异在人类中的分子后果。铁代谢紊乱；以及（c）采用生化方法来揭示 HRG1 的其他上游和下游相互作用因子，这些相互作用因子包括功能性血红素运输网络。我们的目标是全面了解迄今仍存在的介导哺乳动物血红素运输的途径。不太了解。