DIAL

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 这项拟议的研究旨在确定饮食中铁和铁储存的增加是否有助于非裔美国人酒精性肝病的发展。 我们的初步研究表明，高膳食铁导致非洲人和非裔美国人的肝脏铁储备增加，并且增加的肝脏铁储备与饮酒的非洲人的肝功能障碍有关。我们推测，酒精诱导的肝细胞和枯否细胞肝巨噬细胞中的氧化环境导致细胞结肠乌头酸酶/IRP 1的铁簇解聚，并将该酶转化为与铁代谢转录物中的RNA茎环铁应答元件-IRES结合的载脂蛋白。 IRP 1的IRE结合活性的这种非生理性增加反过来导致铁蛋白合成的异常抑制、转铁蛋白受体合成的异常增加以及潜在毒性的细胞质不稳定铁浓度。 基于我们的细胞培养和动物模型的研究，我们进一步假设，增加非血红素铁含量在枯否细胞引发这些细胞的NF-κ B活化和促炎基因表达，从而有助于酒精性肝病的发病机制在非洲裔美国人。 我们的目的是测试两个中心假设：i高膳食铁有助于酒精诱导的倾向异常铁负荷的细胞，和ii增加肝铁contrributes在酒精性肝病的设置肝损伤。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proposed research is designed to determine if increased dietary iron and iron stores contribute to the development of alcholic liver disease in African Americans. Our preliminary studies indicate that high dietary iron leads to increased hepatic iron stores in both Africans and African Americans, and that incrreased hepatic iron stores are associated with hepatic dysfunction in Africans who consume alcohol. We postulate that the oxidative environment induced by alcohol in heptocytes and Kupffer cell (hepatic macrophages) leads to diassembly of the ironfur cluster of cytocolic aconitase/IRP 1 and conversion of this enzyme to an apoprotein that binds to RNA stem loops (iron repsonisve elements-IREs) in iron metabolism transcripts. This non-physiologic increase in IRE-binding activity of IRP1 in turn leads to abnormal repression of ferritin synthesis and abnormal increases in transferrin receptor synthesis and potentially toxic cytosolic labile iron concentrations. Based on our cell culture and animal model studies, we further postulate that increased non-heme iron content in Kupffer cells primes these cell for NF-kB activation and proinflammatory gene expression and thereby contributes to the pathogenesis of alcoholic liver disease in African Americans. We aim to test two central hypotheses: i) high dietary iron contributes to an alcohol induced tendency for abnormal iron-loading of cells, and ii) increased hepatic iron contrributes to liver damage in the setting of alcoholic liver disease.