Effect of Heme on mRNA and miRNA Profile

血红素对 mRNA 和 miRNA 谱的影响

• 批准号: 9096937
• 负责人: HERBERT L BONKOVSKY
• 金额: $ 32.6万
• 依托单位: WINSTON-SALEM STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9096937
• 关键词: Effect; Heme; mRNA; miRNA; Profile

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.

血红素[原核铁]是一种原始的大环，几乎所有生命都依赖于它。它有 流形的已知功能和多样化的特性。正常途径和血红素调节的重要性 新陈代谢的严重性强调了血红素稳态缺陷的严重性。 例如，卟啉是一组疾病，其中正常血红素合成中存在缺陷 主要是为了产生正常卟啉和 血红素合成。基因及其在血红素代谢中特别重要的产物是ALA合酶1 [ALAS1]和血红素氧酶1 [HMOX1]分别是血红素合成的速率控制酶和 分解代谢。羟甲基甲烷合酶[HMBS]是血红素生物合成途径的第三个酶 缺乏急性间歇性卟啉症，这是最严重的急性卟啉症。最近，我们报道 miRNA -122，-196和-LET 7对HMOX1及其关键阻遏物表达的重要新颖作用 Bach1，我们最近发现了蛋白酶体和其他蛋白酶的新的和迄今为止的意外角色 调节ALAS1，BACH1和HMOX1的途径。我们还发现了由 血红素过量与血红素缺乏对人肝细胞中miRNA和mRNA的相互表达的缺乏。 血红素是急性斑岩攻击及其预防的选择的治疗方法 对肝脏，其他组织和器官的有害影响，尤其是反复使用。我们最近 微阵列导致人Huh-7细胞揭示了血红素过剩与血红素缺乏对的新型作用 几种基因和途径。现在重要的是要评估改变的潜在生理重要性 在体外模型中的miRNA和mRNA轮廓中，以及在体内是否发生类似变化的程度， 在AIP的动物模型中，在患有急性卟啉症的人类中。我们假设血红素和其他 金属酚蛋白通过改变选定的microRNA和 mRNA概况我们的具体目的如下：目标＃1：描述效果和机制 因此，选择的microRNA调节ALAS1，HMB和HMOX1和/或其键的表达 人类肝细胞中的调节剂。目标＃2以表征精选的影响 相关剂量的血红素在肝，肾脏，脾脏和小鼠的骨髓上，突变是 类似于在人AIP和AIP患者的外周血单核细胞上看到的 谁接受血红素作为治疗。这些研究的结果将为您提供重要的新见解 血红素在健康和疾病中的歧视和关键功能，以及我们在基本和基础上的理解中 临床水平。