Control of iron absorption by intestinal HIF2 in iron and hematological disorders

与铁有关的疾病影响着全球超过10亿人。肠道铁吸收失调是铁相关疾病的重要组成部分。尽管缺铁性贫血和遗传性血色素沉着症在全身铁水平方面处于铁紊乱谱的两端，但它们引发的肠道反应非常相似。铁的高吸收是由转录因子缺氧诱导因子2α介导的。我们最近展示了一种新的异种组织信号轴，它启动了铁相关疾病中肠道铁吸收的增加：肝脏海普西丁水平下降，导致铁出口商铁转运蛋白稳定；由此产生的肠道铁流入血液触发HIF2α激活，从而导致从肠腔增加铁吸收的前馈循环。我们最近发现，肠道微生物区系产生的代谢产物是HIF2α表达和活性的重要调节因子。微生物代谢产物在铁吸收调节中的作用尚不清楚。此外，在缺铁和遗传性血色病中，HIF2α如何选择性地调节与铁代谢相关的靶基因，而不是它的其他靶基因，仍然是一个谜。第一个靶向HIF2α抑制剂在肾癌患者的临床试验中产生了令人振奋的结果；然而，尚不清楚HIF2α是否可以靶向治疗铁相关疾病。出于这些原因，需要对HIF2α及其在铁代谢中的作用进行研究，并有可能导致新的治疗方法。这项建议的总体目标是确定HIF2α介导的肠道铁吸收调节的机制基础。根据我们的初步数据，我们假设在铁相关疾病中，HIF2α激活的转录活性和铁吸收基因网络受到表观遗传重编程和微生物代谢物的协同调控。利用一种新的报告小鼠模型，我们发现了HIF2α铁靶基因上特异性的组蛋白修饰。在目标1中，我们将使用相同的小鼠模型进行实验，以确定细胞自主的表观遗传重新编程是否对调节肠道铁吸收至关重要。在目标2中，我们将确定微生物代谢物轴是否是铁缺乏和铁超载障碍中调节HIF2α的主要机制。在目标3中，我们将确定抑制或激活HIF2α的药物在铁相关疾病的临床前模型中是否单独或在辅助环境下提供任何益处。这些目标的完成将(I)揭示HIF2α调节的机制，(Ii)确定改变肠道铁吸收的新的代谢途径，以及(Iii)突出新的途径和潜在的药物靶点。

Iron-related disorders affect over a billion people worldwide. Dysregulation of intestinal iron absorption is an essential component of iron-related disorders. Although iron-deficient anemia and hereditary hemochromatosis are on opposite ends of the iron-disorder spectrum with respect to systemic iron levels, they initiate very similar intestinal responses. Hyperabsorption of iron is mediated by the transcription factor hypoxia-inducible factor (HIF)2α. We recently demonstrated a novel hetero-tissue signaling axis that initiates increased intestinal iron absorption in iron-related disorders: liver hepcidin levels decrease, leading to stabilization of the iron exporter ferroportin; the resulting efflux of intestinal iron into the blood triggers HIF2α activation, which leads to a feed-forward cycle of increased iron absorption from the intestinal lumen. We recently found that metabolites produced by gut microbiota are essential regulators of HIF2α expression and activity. The role of the microbial metabolites in the regulation of iron absorption is still unclear. Moreover, how HIF2α selectively regulates iron metabolism-related target genes, but not its other target genes, in iron deficiency and hereditary hemochromatosis is enigmatic. The first on-target HIF2α inhibitor produced promising results in clinical trials with patients with renal cancer; however, it is not known whether HIF2α can be targeted to treat iron-related disorders. For those reasons, research on HIF2α and its role in iron metabolism is needed and likely to lead to novel therapies. The overall objective of this proposal is to define the mechanistic underpinnings of HIF2α-mediated regulation of intestinal iron absorption. On the basis of our preliminary data, we hypothesize that the transcriptional activity and iron-absorptive gene networks activated by HIF2α are regulated in a coordinate fashion by epigenetic reprogramming and microbial metabolites in iron-related disorders. Using a novel reporter mouse model, we discovered specific histone modifications on HIF2α iron target genes. In Aim 1, we will conduct experiments using the same mouse model to determine if cell-autonomous epigenetic reprogramming is critical to regulate intestinal iron absorption. In Aim 2, we will determine if the microbial metabolite axis is the major mechanism regulating HIF2α in iron-deficiency and iron-overload disorders. In Aim 3, we will determine if drugs that inhibit or activate HIF2α provide any benefit alone or in an adjuvant setting in preclinical models of iron-related disorders. Completion of those Aims will (i) uncover mechanisms of HIF2α regulation, (ii) define new metabolic pathways that alter intestinal iron absorption, and (iii) highlight new pathways and potential drug targets.