Defining a novel mechanism of mucosal healing

定义粘膜愈合的新机制

• 批准号: 10094054
• 负责人: Gregory F Sonnenberg
• 金额: $ 49.95万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094054
• 关键词: Address; Adolescent and Young Adult; Affect; American; Antibiotics; Binding; Cell physiology; Cell surface; Chronic; Data; Dendritic Cells; Development; Disease; Exhibits; Functional disorder; Germ-Free; Hepatocyte; Homeostasis; Human; Immune response; Immune system; Impaired wound healing; Impairment; Incidence; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Iron; Knowledge; Liver; Mammals; Microbe; Modeling; Molecular; Mucosal Healing Pathway; Mucous Membrane; Mus; Pathway interactions; Patients; Phenotype; Prevalence; Production; Public Health; Regulation; Research Proposals; Role; Sampling; Source; Testing; Therapeutic; Tissues; absorption; base; cellular targeting; chronic inflammatory disease; dietary; dysbiosis; extracellular; fecal transplantation; gut microbiota; healing; health economics; hepcidin; host microbiota; in vivo; inflammatory disease of the intestine; innovation; intestinal injury; metal transporting protein 1; microbial; microbiota; mouse model; novel; novel strategies; overexpression; peptide hormone; pre-clinical; prevent; promoter; response; simulation; socioeconomics; tissue repair; tool

PROJECT ABSTRACT Chronic inflammatory diseases, such as inflammatory bowel disease (IBD), are a significant socio-economic problem with an accelerating incidence around the world that affects adolescents and young adults. These diseases manifest with chronic dysregulated immune responses that ultimately promote tissue destruction. While most current therapeutic approaches are focused on limiting inflammation, there is an urgent need to develop novel strategies that also facilitate tissue repair and mucosal healing. The fundamental focus of this research proposal is to mechanistically define a novel pathway that promotes mucosal healing in the intestine, and further determine its therapeutic potential in preclinical mouse models. In our preliminary data, we unexpectedly identified that hepcidin, the master regulator of systemic iron homeostasis in mammals, is an essential promoter of mucosal healing in the intestine. Surprisingly, hepatocytes were not the critical cellular source of hepcidin in this context, but rather we identified that dendritic cells (DCs) express hepcidin in response to microbial simulation. Further, we identified that DC-derived hepcidin support mucosal healing by regulating local iron levels and modulating the composition of the intestinal microbiota. These findings provoke the central hypothesis that DC-derived hepcidin is a critical regulator of mucosal healing. We will employ theses approaches and develop innovative tools to define the role and regulation of DC-derived hepcidin during homeostasis or following intestinal damage and inflammation. Three specific aims of this project will determine (i) What DCs express hepcidin and how is DC-derived hepcidin regulated to promote mucosal healing? (ii) How does DC-derived hepcidin mechanistically influence mucosal healing? and (iii) Can hepcidin be therapeutically harnessed to support mucosal healing? Collectively, these studies will mechanistically define the role and regulation of DC-derived hepcidin in basic mouse models and human samples. Further, the proposed studies will provide important pre-clinical evidence on the therapeutic potential of modulating DCs or hepcidin in the context of IBD and other chronic inflammatory diseases.

项目摘要 慢性炎症性疾病，例如炎症性肠病（IBD），是一种重要的社会经济 影响着青少年和年轻人的世界各地加速发病率的问题。这些 疾病表现出慢性失调的免疫反应，最终促进组织破坏。 尽管大多数当前的治疗方法都集中在限制炎症上，但迫切需要 制定新的策略，还可以促进组织修复和粘膜愈合。这个基本重点 研究建议是机械地定义了一种新的途径，该途径促进了粘膜愈合 肠，并进一步确定其在临床前小鼠模型中的治疗潜力。在我们的初步中 数据，我们出乎意料地发现，哺乳动物系统性铁稳态的主要调节剂Hepcidin， 是肠中粘膜愈合的基本启动子。令人惊讶的是，肝细胞并不是关键 在这种情况下，肝素的细胞来源，但我们确定树突状细胞（DCS）在 对微生物模拟的响应。此外，我们确定了DC衍生的Hepcidin支持粘膜愈合 调节局部铁水平并调节肠菌群的组成。这些发现 引起了核心假设，即DC衍生的肝素是粘膜愈合的关键调节剂。我们 将采用这些方法并开发创新工具来定义DC衍生的角色和调节 在体内平衡或肠道损伤和炎症后进行肝素。这三个特定目标 项目将确定（i）DCS表达哪些肝素以及如何受到DC衍生的Hepcidin的调节以促进 粘膜愈合？ （ii）DC衍生的肝素如何影响粘膜愈合？ （iii）可以 在治疗上可以利用肝素来支持粘膜愈合？这些研究总的来说 机械学上定义了DC衍生的肝素在基本小鼠模型和人类中的作用和调节 样品。此外，拟议的研究将为治疗潜力提供重要的临床前证据 在IBD和其他慢性炎症性疾病的背景下调节DC或肝素。