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，如炎症性肠病（IBD），是一个重大的社会经济问题。 这一问题在世界各地的发病率不断上升，影响到青少年和年轻人。这些 疾病表现为慢性失调的免疫应答，其最终促进组织破坏。 虽然目前大多数治疗方法都集中在限制炎症，但迫切需要 开发新的策略，也有利于组织修复和粘膜愈合。这其中的基本焦点 一项研究计划是从机制上确定一种促进粘膜愈合的新途径， 肠，并进一步确定其在临床前小鼠模型中的治疗潜力。在我们的初步调查中 数据，我们意外地鉴定出铁调素，哺乳动物中系统性铁稳态的主要调节剂， 是肠粘膜愈合的重要促进剂。令人惊讶的是，肝细胞不是关键的 在这种情况下，我们认为hepcidin的细胞来源，而是我们确定树突状细胞（DC）表达hepcidin， 对微生物模拟的反应。此外，我们确定DC衍生的铁调素通过以下方式支持粘膜愈合： 调节局部铁水平和调节肠道微生物群的组成。这些发现 激发了DC衍生的铁调素是粘膜愈合的关键调节剂的中心假设。我们 将采用这些方法，并开发创新的工具，以确定DC衍生的作用和监管 在体内平衡期间或在肠损伤和炎症之后使用铁调素。三个具体目标 该项目将确定（i）什么样的DC表达hepcidin以及如何调节DC衍生的hepcidin以促进 粘膜愈合(ii)DC衍生的hepcidin如何机械地影响粘膜愈合？（三）可以 hepcidin可以治疗性地用于支持粘膜愈合吗？这些研究将 在基础小鼠模型和人类模型中， 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hepcidin。