The long-term goals of this proposal are to delineate how humans regulate and integrate heme homeostasis at the organismal level. Heme, an iron containing organic ring, functions as a vital cofactor responsible for diverse biological functions in addition to serving as the major source of bioavailable iron in human nutrition. Heme is a hydrophobic and cytotoxic cofactor synthesized in the mitochondria although acceptor hemoproteins reside in different cellular compartments. How is heme transported through cellular membranes and organelles? In the previous grant cycle, we pioneered the use of Caenorhabditis elegans, a genetic animal model which does not synthesize heme but utilizes environmental heme to manufacture hemoproteins, to identify seven new molecules and establish a model for heme homeostasis and trafficking in animals. In the next funding cycle, we will employ innovative tools developed in the previous grant cycle to bridge significant knowledge gaps in delineating how tissues and cells communicate their heme status to regulate organismal heme homeostasis in live animals. Although a systemic heme communication and transport system may be expected in C. elegans, a heme auxotroph, several lines of evidence in humans, mice and zebrafish indicate that such pathways must also exist in vertebrates. Herein, we propose to elucidate the mechanisms of inter-tissue communication and identify the molecular identity of the heme signal using C. elegans. The studies in this proposal will test the hypothesis that HRG-7 and HRG-8 communicate and integrate intestinal heme status with extraintestinal tissues by initiating a feedback response to regulate systemic heme homeostasis. To elucidate the mechanisms of HRG-7 function at the molecular and organismal level, we will determine if catalytic activity, intestinal secretion, and subcellular location of HRG-7 is essentil for systemic heme homeostasis. To elucidate the mechanisms of HRG-8 function at the molecular and organismal level, we will define its genetic requirement by functional complementation of hrg-8 mutants using ectopically expressed and membrane anchored versions of HRG-8, and assess the inter-dependence of HRG-8 and HRG-7 for heme signaling function. To identify the molecular interactors or substrates of HRG-7 and HRG-8, we will use multidimensional protein identification technology, validate candidate interactors with RNAi knockdown, and specifically characterize interactors which have homologs in humans. Our studies in C. elegans will overcome several obstacles posed by mammalian model systems namely the control of intracellular heme levels by external means, experimental manipulation of animals at subcellular resolution, and optical transparency for in vivo monitoring of heme signals between tissues during development. Our proposed project is transformative because the molecules and mechanisms for trafficking and distribution of heme to regulate systemic heme homeostasis in eukaryotes are largely unknown. Results from our studies may provide a heuristic paradigm to tackle similar questions for other micronutrients.

Public Health Relevance

Iron deficiency is the world's number one nutritional disorder, and heme is the most bioavailable form of iron for human consumption. Identification of how dietary heme is transported and coordinated with systemic heme levels will permit the design of synthetic heme-based nutraceuticals specifically targeted to iron-deficient individuals. Iron deficiency is exacerbated by blood-loss due to heme auxotrophic parasites such as intestinal hookworms which depend on host heme to survive. A drug that targets the heme transport and regulatory pathway in helminths would be a powerful anthelminthic. Thus, identification of heme trafficking pathways across species will have a profound and long-lasting impact on our understanding of fundamental, clinical and applied processes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Maruvada, Padma
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University of Maryland College Park
Veterinary Sciences
Schools of Earth Sciences/Natur
College Park
United States
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Sinclair, Jason; Pinter, Katherine; Samuel, Tamika et al. (2017) Inter-organ signalling by HRG-7 promotes systemic haem homeostasis. Nat Cell Biol 19:799-807
Soares, Miguel P; Hamza, Iqbal (2016) Macrophages and Iron Metabolism. Immunity 44:492-504
Luck, Ashley N; Yuan, Xiaojing; Voronin, Denis et al. (2016) Heme acquisition in the parasitic filarial nematode Brugia malayi. FASEB J 30:3501-3514
Yuan, Xiaojing; Rietzschel, Nicole; Kwon, Hanna et al. (2016) Regulation of intracellular heme trafficking revealed by subcellular reporters. Proc Natl Acad Sci U S A 113:E5144-52
Korolnek, Tamara; Hamza, Iqbal (2015) Macrophages and iron trafficking at the birth and death of red cells. Blood 125:2893-7
Korolnek, Tamara; Zhang, Jianbing; Beardsley, Simon et al. (2014) Control of metazoan heme homeostasis by a conserved multidrug resistance protein. Cell Metab 19:1008-19
Samuel, Tamika K; Sinclair, Jason W; Pinter, Katherine L et al. (2014) Culturing Caenorhabditis elegans in axenic liquid media and creation of transgenic worms by microparticle bombardment. J Vis Exp :e51796
Yuan, Xiaojing; Fleming, Mark D; Hamza, Iqbal (2013) Heme transport and erythropoiesis. Curr Opin Chem Biol 17:204-11
Huynh, Chau; Yuan, Xiaojing; Miguel, Danilo C et al. (2012) Heme uptake by Leishmania amazonensis is mediated by the transmembrane protein LHR1. PLoS Pathog 8:e1002795
Chen, Caiyong; Samuel, Tamika K; Krause, Michael et al. (2012) Heme utilization in the Caenorhabditis elegans hypodermal cells is facilitated by heme-responsive gene-2. J Biol Chem 287:9601-12

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