Regulation of Iron Homeostasis by BMP Signaling

摘要 铁的体内平衡受到严格的调节，为生长和生存提供这种关键元素，但 防止铁过量的毒性。全身铁平衡调节异常导致常见疾病 包括贫血和铁超负荷紊乱遗传性血色病。铁调素是一种主要的调节剂， 通过下调铁输出蛋白的细胞表面表达发挥作用的全身铁平衡 ferroportin来控制从饮食中的铁吸收和从身体储存中的铁释放。但 铁水平被肝脏感知以调节铁调素表达的机制还不完全清楚， 明白我们以前已经证明，1）血Juvelin（HJV）是骨的共受体 形态发生蛋白（BMP）-SMAD信号通路是铁调素的一个重要转录调节因子 2）BMP 6是HJV调节hepcidin表达的关键内源性配体 和全身铁平衡，3）BMP-SMAD信号通路对铁调素通过铁的调节至关重要，4） 铁激活BMP-SMAD通路至少有两种机制：肝铁诱导肝细胞凋亡， BMP 6 mRNA表达和循环铁刺激BMP 6下游的SMAD信号传导，5）BMP-6的表达和循环铁刺激SMAD信号传导。 SMAD信号通路与大多数其他已知的铁调素调节通路交叉，包括 血色病蛋白HFE和TFR 2与炎症，以及6）BMP-SMAD途径的调节剂 调节hepcidin表达治疗慢性疾病血色素沉着症和贫血的动物模型。 这些研究已经对血色病的病理生理学产生了重要的见解， 将BMP-SMAD通路确定为铁紊乱的新治疗靶点。在这场竞争性的复兴中， 我们将解决关于铁如何被肝脏感知以调节铁调素的重要的未回答的问题， 以及BMP-SMAD通路在这一过程中的关键作用。在具体目标I中，我们将使用我们的新颖条件 在特定肝细胞群中的Bmp 6 KO小鼠，以确定调节 hepcidin表达，我们将使用体外方法与体内生物发光测定一起， 小鼠，以阐明铁介导的BMP 6诱导的分子机制。在具体目标II中，我们 将使用体内遗传和药理学方法，结合生物化学和细胞培养研究， 鉴定BMP-SMAD信号级联中对铁调素至关重要的其他特定功能组分 调节和铁稳态。这个项目的长期目标是了解BMP的作用 信号通路在调节铁调素表达和全身铁平衡中的作用，以深入了解铁调素的作用机制。 铁稳态在健康和疾病的生理学和病理生理学，并最终开发新的 用于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.