Modulation of Hepcidin-Ferroportin Signaling using Small Molecules

描述(申请人提供)：海普西丁是一种最近被描述的激素，在铁代谢中发挥关键作用。海普西丁针对铁蛋白进行降解，从而减少巨噬细胞和肠细胞中铁的输出。炎症介质诱导的海普西丁的产生减少了红细胞生成所需的铁的供应，从而导致炎症贫血。PI结合了他们在化学生物学和疾病建模方面的专业知识，研究了骨形态发生蛋白(BMP)信号如何调节海普西丁和铁蛋白的表达。该团队的成就包括发现了第一个BMP信号的小分子抑制剂，并证明了这些抑制剂可以在动物模型中治疗炎症贫血。最近，很明显，BMP-海普西丁-铁蛋白信号通路可以导致炎症性疾病，而不是典型的铁稳态异常，包括动脉粥样硬化。在这一新的应用中，PI建议继续使用遗传学和化学生物学来研究铁的动态平衡，新的重点是海普西丁-铁门蛋白信号在巨噬细胞功能中的作用以及这一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简便的遗传和药物操作来表征海普西丁-铁门蛋白信号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建议采取互补的方法来阐明在患有动脉粥样硬化的转基因小鼠中，通过海普西丁-铁门蛋白-铁信号对巨噬细胞功能的调节。最后，在目标3中，Pis将使用转基因斑马鱼进行体内筛选，以确定在海普西丁存在的情况下稳定铁门蛋白的新的小分子。稳定铁孔蛋白的化合物将在小鼠身上进行效力、特异性和保护作用的评估。这项拟议的研究计划将为研究海普西丁-铁门蛋白-铁信号在巨噬细胞功能和炎症性疾病中的作用提供重要的见解，以及新的斑马鱼和小鼠模型和小分子探针。此外，稳定铁蛋白的小分子的鉴定可能代表着治疗炎症性疾病的新的治疗剂，包括动脉粥样硬化性心血管疾病。

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.