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

铁和血液系统疾病中肠道 HIF2 控制铁吸收

基本信息

批准号：
10507519
负责人：
YATRIK M SHAH
金额：
$ 5.79万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10507519
关键词：
Adjuvant Affect Anemia Antibodies Binding Blood Cells Chronic Kidney Failure Clear cell renal cell carcinoma Clinical Trials Data Disease Drug Targeting Elements Epigenetic Process Epithelial Genes Genetic Transcription Grant HIF1A gene Hematological Disease Hemochromatosis Hepatic Hereditary hemochromatosis Homeostasis Hormones Hydrophobicity Hypoxia Inducible Factor Intestinal Absorption Intestines Iron Iron Metabolism Disorders Iron Overload Iron deficiency anemia Lead Ligand Binding Liver diseases Mediating Membrane Proteins Metabolic Pathway Mus Pathway interactions Patients Persons Pharmaceutical Preparations Physiological Play Pre-Clinical Model Proteins Publishing Regulation Renal carcinoma Reporter Research Role Signal Transduction Testing Tissues Transgenic Organisms Work base clinically relevant druggable target effective therapy epigenetic regulation experimental study gene network gut microbiota hepcidin histone modification in vivo inhibitor iron absorption iron deficiency iron metabolism metal transporting protein 1 microbial microbiota mouse model novel novel therapeutics promoter response sensor tool transcription factor

项目摘要

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.

铁相关疾病影响着全世界超过十亿人，尽管缺铁性贫血和遗传性血色素沉着症处于铁紊乱谱系的两端，但肠道铁吸收失调是铁相关疾病的重要组成部分。，它们启动非常相似的肠道反应，由转录因子缺氧诱导因子 (HIF)2α 介导。我们最近证明了一种新的异源组织信号轴，可启动肠道铁吸收增加。铁相关疾病：肝脏铁调素水平降低，导致铁转运蛋白稳定；由此产生的肠道铁流入血液触发 HIF2α 激活，从而导致肠腔铁吸收增加的前馈循环。最近发现肠道微生物群产生的代谢物是HIF2α表达和活性的重要调节剂，而且微生物代谢物在铁吸收调节中的作用仍不清楚。在铁缺乏和遗传性血色素沉着症中，HIF2α 选择性地调节铁代谢相关的靶基因，但不调节其他靶基因，这一点令人费解。第一个靶向 HIF2α 抑制剂在肾癌患者的临床试验中取得了令人鼓舞的结果，但事实并非如此。由于这些原因，需要对 HIF2α 及其在铁代谢中的作用进行研究，并且可能会带来新的治疗方法。该提案的总体目标是确定 HIF2α 是否可以靶向治疗铁相关疾病。 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，我们发现HIF2α激活的转录活性和铁吸收基因网络通过表观遗传重编程和铁中的微生物代谢物以协调方式调节。使用新型报告小鼠模型，我们发现了 HIF2α 铁靶基因的特定组蛋白修饰。在目标 1 中，我们将使用相同的小鼠模型进行实验以确定是否存在这种修饰。细胞自主表观遗传重编程对于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轴是否是铁缺乏和铁过载疾病中调节 HIF2α 的主要机制。抑制或激活 HIF2α 的药物可以单独或在铁相关疾病的临床前模型中提供辅助作用，完成这些目标将 (i) 揭示铁相关疾病的机制。 HIF2α 调节，(ii) 定义改变肠道铁吸收的新代谢途径，(iii) 突出新途径和潜在药物靶点。