Modulation of Hepcidin-Ferroportin Signaling using Small Molecules

描述（由申请人提供）：铁调素是最近描述的在铁代谢中起关键作用的激素。铁调素靶向膜铁转运蛋白进行降解，从而减少铁从巨噬细胞和肠细胞的输出。炎症介质诱导铁调素产生降低了红细胞生成的铁可用性，导致炎症性贫血。PI结合了他们在化学生物学和疾病建模方面的专业知识，研究骨形态发生蛋白（BMP）信号传导如何调节铁调素和铁转运蛋白的表达。该团队的成就包括发现第一个BMP信号传导的小分子抑制剂，并证明这些抑制剂可以治疗动物模型中的炎症贫血。最近，BMP-铁调素-膜铁转运蛋白信号传导途径可以导致通常不归因于铁稳态异常的炎性疾病，包括动脉粥样硬化，这一点已经变得很明显。在这项更新申请中，PI建议继续使用遗传学和化学生物学来研究铁稳态，新的重点是铁调素-膜铁转运蛋白信号在巨噬细胞功能中的作用以及这种信号通路在健康和疾病中的作用。提出了三个目标。在目标1中，PI将利用透明斑马鱼中的简易遗传和药理学操作来表征铁调素-膜铁转运蛋白信号传导和铁状态在巨噬细胞发育、迁移和吞噬中的作用。在目标2中，PI建议采取互补方法来阐明在患有动脉粥样硬化的基因修饰小鼠中通过铁调素-膜铁转运蛋白-铁信号转导对巨噬细胞功能的调节。最后，在目标3中，PI将使用转基因斑马鱼进行体内筛选，以鉴定在铁调素存在下稳定膜铁转运蛋白的新型小分子。将评价铁转运蛋白稳定化合物在小鼠中的效力、特异性和效果保持。拟议的研究计划将为铁调素-膜铁转运蛋白-铁信号在巨噬细胞功能和炎症性疾病中的作用提供重要见解，以及新的斑马鱼和小鼠模型和小分子探针。此外，鉴定稳定膜铁转运蛋白的小分子可能代表用于治疗炎性疾病（包括动脉粥样硬化性心血管疾病）的新型治疗剂。

DESCRIPTION (provided by applicant): Hepcidin is a recently described hormone that plays a critical role in iron metabolism. Hepcidin targets ferroportin for degradation thereby reducing export of iron from macrophages and enterocytes. Induction of hepcidin production by inflammatory mediators reduces iron availability for erythropoiesis leading to the anemia of inflammation. The PIs have combined their expertise in chemical biology and disease modeling to investigate how bone morphogenetic protein (BMP) signaling regulates hepcidin and ferroportin expression. The team's accomplishments include discovery of the first small molecule inhibitors of BMP signaling and demonstration that these inhibitors can treat anemia of inflammation in animal models. More recently, it has become apparent that the BMP-hepcidin-ferroportin signaling pathway can contribute to inflammatory diseases not typically attributed to abnormalities of iron homeostasis, including atherosclerosis. In this renewal application, the PIs propose to continue using genetics and chemical biology to study iron homeostasis, with a new focus on the role of hepcidin-ferroportin signaling in macrophage function and the role of this signaling pathway in health and disease. Three aims are proposed. In Aim 1, the PIs will take advantage of facile genetic and pharmacological manipulations in transparent zebrafish to characterize the role of hepcidin-ferroportin signaling and iron status in macrophage development, migration, and phagocytosis. In Aim 2, the PIs propose to undertake complementary approaches to elucidate the regulation of macrophage function by hepcidin-ferroportin-iron signaling in genetically-modified mice with atherosclerosis. Finally, in Aim 3, th PIs will undertake an in vivo screen using transgenic zebrafish to identify novel small molecules that stabilize ferroportin in the presence of hepcidin. Ferroportin-stabilizing compounds will be evaluated for potency, specificity, and conservation of effect in mice. The proposed research program will provide important insights into the roles of hepcidin-ferroportin-iron signaling in macrophage function and inflammatory diseases, as well as new zebrafish and mouse models and small molecule probes. Moreover, the identification of small molecules that stabilize ferroportin may represent novel therapeutic agents for the treatment of inflammatory diseases, including atherosclerotic cardiovascular disease.