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（由适用提供）：该提案的长期目标是定义人类营养中血红素稳态的细胞和分子决定剂。血红素是吸收血红素铁和血红素铁被回收的巨噬细胞的肠上皮细胞生物利用铁的重要来源。在人类肠道中，饮食血红素比无机铁更容易吸收，并且是西方饮食中大多数人体铁的来源。此外，超过70％的总体铁作为血红蛋白中的血红素存在。血红素的铁通过巨噬细胞吞噬体中的感觉红细胞的吞噬作用而回收。到目前为止，在人类肠道中导致血红素转运的基因和途径仍然很差。作为疏水性和细胞毒性辅助因子，必须通过特定的细胞内和细胞间途径以高度控制的方式通过膜运输血红素。在最后一个资金期之前，纽约血红素进口商的身份尚不清楚。我们确定round虫秀丽隐杆线虫是识别血红素传输途径的出色动物模型，因为它与人类同源物合成了大量的血op蛋白，但没有合成血红素de。通过在上一个赠款周期中利用秀丽隐杆线虫的血红素合子，我们成功地确定了第一个真核血红素进口商/转运蛋白HRG1及其相应的人类同源物，这是一个发现的发现，它为动物中的血红素运输和运输提供了第一个初步框架。 HRG1对于巨噬细胞铁的稳态至关重要，在感觉RBCS的吞噬作用期间将血红素从吞噬体转运到细胞质 - 这一过程称为红细胞吞噬作用（细胞代谢，2013年）。重要的是，我们的研究表明，人类中的HRG1变体在血红素转运中有缺陷。该提案中的研究旨在阐明HRG1在分子，细胞和有机水平上通过HRG1运输的精确机制。我们试图检验以下假设：HRG1是难以捉摸的人类血红素转运蛋白，也是基本血红素贩运网络的一部分。我们将利用（a）一种细胞生物学方法来建立HRG1为肠血红素转运蛋白； （b）一种阐明人铁代谢疾病中HRG1变异的分子后果的遗传学方法； （c）一种生化方法，可揭示HRG1完成功能性血红素运输网络的其他上游和下游相互作用。我们的目标是对哺乳动物中媒体血红素运输的途径进行全面的了解，而迄今为止，哺乳动物中的哺乳动物中仍然了解不多的哺乳动物。