Heme [iron protoporphyrin] is a primordial macrocycle upon which nearly all life on earth depends. It has manifold known functions and diverse properties. The importance of a normal pathway and regulation of heme metabolism is underscored by the seriousness of diseases in which there are defects in heme homeostasis. For example, the porphyrias are a group of diseases in which there are defects in normal heme synthesis, due mainly to inborn errors of metabolism that produce deficient activities of the enzymes of normal porphyrin and heme synthesis. Genes and their products of particular importance in heme metabolism are ALA synthase 1 [ALAS1] and heme oxygenase 1 [HMOX1], respectively, the rate-controlling enzymes of heme synthesis and catabolism. Hydroxymethylbilane synthase [HMBS], the third enzyme of the heme biosynthetic pathway, is deficient in acute intermittent porphyria, the most severe of the acute porphyrias. Recently, we reported important novel effects of miRNAs-122, -196, and -let 7 on expression of HMOX1 and its key repressor BACH1, and we recently discovered new and heretofore unexpected roles of proteasomal and other protease pathways that regulate levels of ALAS1, BACH1, and HMOX1. We also have discovered changes caused by heme excess vs heme deficiency on reciprocal expression of miRNAs and mRNAs in human hepatocytes. Heme, which is the treatment of choice for acute porphyric attacks and for their prevention, may have deleterious effects on the liver and other tissues and organs, especially with repeated use. Our recent microarray results in human Huh-7 cells have unveiled novel effects of heme excess vs heme deficiency on several genes and pathways. It is important now to assess the potential physiological importance of alterations in miRNA and mRNA profiles in in vitro models and whether and to what extent similar changes occur in vivo, in animal models of AIP and in humans with acute porphyrias. We hypothesize that heme and other metalloporphyrins regulate ALAS1, HMBS and HMOX1 expression by altering selected microRNAs and mRNA profiles Our specific aims are as follows:
Aim #1 : To delineate effects and mechanisms whereby selected microRNAs modulate expression of ALAS1, HMBS, and HMOX1 and/or their key regulators in human hepatocytes.
Aim #2 To characterize the effects of selected, physiologically relevant doses of heme on the livers, kidneys, spleens, and bone marrows of mice with mutations that resemble those seen in human AIP and on peripheral blood mononuclear cells of patients with AIP who are receiving heme as therapy. Results of these studies will provide important new insights into the manifold and critical functions of heme in health and disease, and in our understanding at both the basic and clinical level.
Heme is a molecule formed from iron and protoporphyrin upon which most life on earth depends. Heme is what makes our blood red. It helps our hemoglobin to carry oxygen to our tissues and carbon dioxide away from our tissues. Normally, levels of heme in our tissues are closely regulated: Excesses of heme cause decreases in new heme synthesis and increases in heme breakdown. How heme does this is not well understood. In addition, there are a group of diseases called porphyrias in which heme synthesis is deficient and/or in which potentially toxic precursors of heme accumulate. Some of these diseases can be treated by giving heme intravenously, but excess heme, too, may be toxic. In this project, we plan to discover how heme exerts its beneficial, as well as its toxic effects, in order to improve our knowledge of the manifold effects of this primordial molecule and in order to improve the health and well-being of patients with porphyria.
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