Heme Homeostasis

我们与马里兰州大学的Hamza实验室合作，利用C. elegans以确定血红素摄取和运输的新因素。 使用基因表达微阵列为基础的方法，我们确定了基因的表达变化的生物可利用血红素浓度的变化。 我们发现，两个基因，编码HRG-1和HRG-4，是必不可少的血红素稳态和正常发育。 我们证明，血红素缺乏上调hrg-1及其进化上保守的paramericallyhrg-4的表达。 在蠕虫中HRG-1或HRG-4的消耗导致有机体血红素感测的破坏和对血红素类似物的异常反应。 HRG-1和HRG-4是新的跨膜蛋白，结合血红素并具有进化上保守的功能。 斑马鱼中hrg-1的瞬时敲低导致脑积水、卵黄管畸形，并且最引人注目的是，导致红细胞生成的严重缺陷-这些表型完全被蠕虫HRG-1拯救。 这些发现揭示了未预料到的和保守的途径，细胞血红素贩运动物，定义的范式真核血红素运输。 揭示了C.线虫将为人类血红素代谢紊乱提供新的见解，并产生独特的驱虫剂来对抗蠕虫感染。 现在的工作是针对进一步了解这些因素的血红素调节的分子细节，并表征我们的分析确定的许多其他基因。

In collaboration with the Hamza lab at the University of Maryland, we exploited the heme auxotrophy of C. elegans to identify novel factors for heme uptake and trafficking. Using a gene expression microarray-based approach, we identified genes that changed expression in response to changing concentrations of bioavailable heme. We found that two genes, encoding HRG-1 and HRG-4, are essential for heme homeostasis and normal development. We demonstrate that heme deficiency up regulates expression of hrg-1 and its evolutionarily conserved paralog hrg-4. Depletion of either HRG-1 or HRG-4 in worms results in disruption of organismal heme sensing and abnormal response to heme analogs. HRG-1 and HRG-4 are novel transmembrane proteins that bind heme and have evolutionarily conserved functions. Transient knockdown of hrg-1 in zebrafish leads to hydrocephalus, yolk tube malformations, and, most strikingly, profound defects in erythropoiesis - phenotypes that are fully rescued by worm HRG-1. These findings reveal unanticipated and conserved pathways for cellular heme trafficking in animals that define the paradigm for eukaryotic heme transport. Uncovering the mechanisms of heme transport in C. elegans will provide novel insights into human disorders of heme metabolism and generate unique anthelmintics to combat worm infestations. Work is now directed at further understanding the molecular details of heme regulation by these factors and characterizing the many other genes identified by our analysis.