Immune regulation of tissue iron in health and disease

项目摘要 贫血和炎症通常在慢性疾病中并存，包括炎症性肠病(IBD)， 感染和癌症。在这些疾病中，贫血往往难以治疗，而贫血和 贫血治疗对疾病结果的影响并不明确。因此，有一种重大的医学需求 更好地了解贫血和炎症性疾病之间的因果联系。定义最好的链接之一 介于贫血和炎症之间的是一种名为海普西丁的多肽荷尔蒙，它严重抑制铁的释放 从细胞内存储。在炎症期间，海普西丁的水平通常会急剧上升，并可能导致 一种形式的贫血称为炎症性贫血(AI)。相反，炎症性疾病与 大量出血导致一种独特的贫血形式，称为缺铁性贫血(IDA)，在这种贫血中，海普西丁 标高将被抑制。这项研究建议的根本重点是：i.)调查影响 海普西丁对炎症性疾病的作用。表达海普西丁及其蛋白的细胞群体的鉴定 炎症过程中的伙伴铁蛋白，以及III.)通过不同的方式确定铁调制的影响 细胞群对炎症性疾病的消解作用。我将采用创新的技术 确定海普西丁和铁蛋白在化学诱导中的作用的方法和新工具的开发 肠道损伤、肠道感染和炎症引发的癌症。总体而言，这些结果 研究将确定铁的新型细胞介质在体内的调节和功能意义 肠子。这些发现将为正在进行的针对组织的治疗方法的开发提供关键信息。 在炎症性疾病背景下的修复和贫血。

PROJECT ABSTRACT Anemia and inflammation often co-occur in chronic diseases including inflammatory bowel disease (IBD), infection, and cancer. Anemia is often refractory to treatment in these diseases, and the impact of anemia and anemia therapies on disease outcome is poorly defined. Accordingly, there is a significant medical need to better understand the causal links between anemia and inflammatory diseases. One of the best defined links between anemia and inflammation is a peptide hormone called hepcidin, which critically inhibits iron release from intracellular stores. Hepcidin levels typically increase dramatically during inflammation, and can cause one form of anemia termed anemia of inflammation (AI). Conversely, inflammatory diseases associated with heavy bleeding cause a distinct form of anemia known as iron deficiency anemia (IDA), in which hepcidin levels are suppressed. The fundamental focus of this research proposal is to: i.) investigate the impact of hepcidin on inflammatory disease, ii.) identify cellular populations expressing hepcidin and its partner ferroportin during inflammation, and iii.) determine the impact of iron modulation by distinct cellular population on the resolution of inflammatory diseases. I will employ innovative technical approaches and develop new tools to define the role of hepcidin and ferroportin during chemically-induced intestinal damage, intestinal infection, and in inflammation-induced cancer. Collectively, results from these studies will define the regulation and functional significance of novel cellular mediators of iron within the intestine. These findings will critically inform ongoing efforts to develop therapies targeting tissue repair and anemia in the context of inflammatory diseases.