Regulation of Iron Homeostasis by BMP Signaling

摘要 铁稳态受到严格调控，以提供这一生长和生存的关键因素，但 防止铁过量的毒性。全身铁平衡调节异常导致常见病 包括贫血和铁超载紊乱遗传性血色素沉着症。海普西丁是一种主要的调节剂 通过下调铁输出器的细胞表面表达而起作用的全身铁平衡 铁蛋白可以控制饮食中铁的吸收和体内储存中铁的释放。然而， 肝脏感知铁水平以调节海普西丁表达的机制还不完全 明白了。我们以前已经证明：1)血凝素(HJV)是骨骼的共同受体 形态发生蛋白(BMP)-SMAD信号通路，是海普西丁的中枢转录调节因子 在肝脏中的表达，2)Bmp6是HJV在调节海普西丁表达中的关键内源性配体 和全身铁平衡，3)BMP-SMAD信号通路在铁对海普西丁的调节中起关键作用，4) 铁激活BMP-SMAD途径至少有两种机制：肝铁诱导肝脏 Bmp6的mRNA表达和循环铁刺激Bmp6下游的SMAD信号，5)BMP- Smad信号通路与大多数已知的海普西丁调节通路相交，包括 血色沉着症蛋白HFE和TFR2与炎症，以及6)BMP-SMAD途径的调节物 调节海普西丁表达治疗慢性疾病血色素沉着症和贫血动物模型。 这些研究已经对血色素沉着症的病理生理学产生了重要的见解，并 确定BMP-SMAD途径是治疗铁紊乱的新靶点。在这场竞争性的更新中， 我们将解决一些重要的悬而未决的问题，即铁是如何被肝脏感知来调节海普西丁的， 以及BMP-SMAD通路在这一过程中的关键作用。在特定的目标I中，我们将使用我们的小说条件 Bmp6 KO小鼠在特定肝细胞群中确定调节Bmp6的细胞来源 海普西丁的表达，我们将使用体外方法结合体内生物发光分析 以阐明铁介导的Bmp6诱导的分子机制。在第二个具体目标中，我们 将使用体内的遗传和药理学方法，结合生化和细胞培养研究来 确定BMP-SMAD信号级联中对海普西丁至关重要的其他特定功能组件 调节和铁稳态。该项目的长期目标是了解BMP的作用 调节海普西丁表达和系统铁平衡的信号通路，以了解 铁的生理学和病理生理学在健康和疾病中的动态平衡，并最终发展出新的 治疗铁代谢紊乱的治疗策略。

ABSTRACT Iron homeostasis is tightly regulated to provide this critical element for growth and survival, but to prevent the toxicity of iron excess. Abnormal regulation of systemic iron balance leads to common diseases including anemia and the iron overload disorder hereditary hemochromatosis. Hepcidin is a master regulator of overall body iron balance that acts by downregulating the cell-surface expression of the iron exporter ferroportin to control iron absorption from the diet and iron release from body stores. However, the mechanisms by which iron levels are sensed by the liver to regulate hepcidin expression are not fully understood. We have previously demonstrated that 1) hemojuvelin (HJV) is a co-receptor for the bone morphogenetic protein (BMP)-SMAD signaling pathway, which is a central transcriptional regulator of hepcidin expression in the liver, 2) BMP6 is a key endogenous ligand of HJV in the regulation of hepcidin expression and systemic iron balance, 3) the BMP-SMAD signaling pathway is critical to hepcidin regulation by iron, 4) there are at least two mechanisms by which iron activates the BMP-SMAD pathway: liver iron induces liver BMP6 mRNA expression and circulating iron stimulates SMAD signaling downstream of BMP6, 5) the BMP- SMAD signaling pathway intersects with most other known hepcidin regulatory pathways including the hemochromatosis proteins HFE and TFR2 and inflammation, and 6) modulators of the BMP-SMAD pathway regulate hepcidin expression to treat hemochromatosis and anemia of chronic disease in animal models. These studies have already yielded important insights into the pathophysiology of hemochromatosis and have identified the BMP-SMAD pathway as a novel therapeutic target for iron disorders. In this competing renewal, we will address important unanswered questions about how iron is sensed by the liver to regulate hepcidin, and the key role of the BMP-SMAD pathway in this process. In Specific Aim I, we will use our novel conditional Bmp6 KO mice in specific liver cell populations to determine the cellular source of BMP6 that regulates hepcidin expression, and we will use in vitro approaches together with an in vivo bioluminescence assay in mice to elucidate the molecular mechanisms underlying iron-mediated BMP6 induction. In Specific Aim II, we will use genetic and pharmacologic approaches in vivo coupled with biochemical and cell culture studies to identify other specific functional components of the BMP-SMAD signaling cascade that are critical for hepcidin regulation and iron homeostasis. The long-term goals of this project are to understand the role of the BMP signaling pathway in regulating hepcidin expression and systemic iron balance, to gain insights into the physiology and pathophysiology of iron homeostasis in health and disease, and ultimately to develop new therapeutic strategies for treating disorders of iron metabolism.