Heme [iron protoporphyrin] is a primordial macrocycle upon which nearly all life on earth depends. It hasmanifold known functions and diverse properties. The importance of a normal pathway and regulation of hememetabolism 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, duemainly to inborn errors of metabolism that produce deficient activities of the enzymes of normal porphyrin andheme 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 andcatabolism. Hydroxymethylbilane synthase [HMBS], the third enzyme of the heme biosynthetic pathway, isdeficient in acute intermittent porphyria, the most severe of the acute porphyrias. Recently, we reportedimportant novel effects of miRNAs-122, -196, and -let 7 on expression of HMOX1 and its key repressorBACH1, and we recently discovered new and heretofore unexpected roles of proteasomal and other proteasepathways that regulate levels of ALAS1, BACH1, and HMOX1. We also have discovered changes caused byheme 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 havedeleterious effects on the liver and other tissues and organs, especially with repeated use. Our recentmicroarray results in human Huh-7 cells have unveiled novel effects of heme excess vs heme deficiency onseveral genes and pathways. It is important now to assess the potential physiological importance of alterationsin 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 othermetalloporphyrins regulate ALAS1, HMBS and HMOX1 expression by altering selected microRNAs andmRNA profiles Our specific aims are as follows:
Aim #1 : To delineate effects and mechanismswhereby selected microRNAs modulate expression of ALAS1, HMBS, and HMOX1 and/or their keyregulators in human hepatocytes.
Aim #2 To characterize the effects of selected, physiologicallyrelevant doses of heme on the livers, kidneys, spleens, and bone marrows of mice with mutations thatresemble those seen in human AIP and on peripheral blood mononuclear cells of patients with AIPwho are receiving heme as therapy. Results of these studies will provide important new insights into themanifold and critical functions of heme in health and disease, and in our understanding at both the basic andclinical level.
Brief NarrativeHeme is a molecule formed from iron and protoporphyrin upon which most life on earthdepends. Heme is what makes our blood red. It helps our hemoglobin to carry oxygento our tissues and carbon dioxide away from our tissues. Normally; levels of heme in ourtissues are closely regulated: Excesses of heme cause decreases in new hemesynthesis and increases in heme breakdown. How heme does this is not wellunderstood. In addition; there are a group of diseases called porphyrias in which hemesynthesis 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; aswell as its toxic effects; in order to improve our knowledge of the manifold effects of thisprimordial molecule and in order to improve the health and well-being of patients withporphyria.
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