Novel mechanisms protecting the gut from TNF

保护肠道免受 TNF 侵害的新机制

基本信息

批准号：
10752940
负责人：
Gregory F Sonnenberg
金额：
$ 65.11万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-18 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752940
关键词：
Address American Automobile Driving Biological Birth Cell Death Cell Death Induction Cell Nucleus Cell Survival Cells Cellular biology Chronic Chronic Disease Clinical Research Critical Pathways Cytoplasmic Tail Data Dinoprostone Disease Epithelial Cells Epithelium Equilibrium Exhibits Experimental Models Gastrointestinal tract structure Genes Growth Factor Health Hematopoietic Homeostasis Host Defense Human Immune Immunity Immunology Inflammation Inflammatory Inflammatory Bowel Diseases Interleukins Intestinal Neoplasms Intestines Investigation Knowledge Lymphocyte Lymphoid Cell Mediating Modeling Molecular Mus Nature Nuclear Export Nuclear Translocation Organoids Outcome Pathogenesis Pathologic Pathway interactions Patients Predisposition Production Prostaglandin Production Prostaglandin Receptor Prostaglandins Proteolytic Processing Publishing Regulation Role Sampling Shapes Signal Transduction Source TNF gene Testing Therapeutic Tissues Translating ZNF145 gene autocrine cell motility chronic inflammatory disease curative treatments cytokine experimental study gut inflammation health economics heparin-binding EGF-like growth factor interleukin-22 intestinal epithelium microbial mouse model novel novel therapeutics overexpression protective pathway receptor response single-cell RNA sequencing socioeconomics tissue regeneration translational study treatment strategy

项目摘要

PROJECT ABSTRACT Tumor necrosis factor (TNF) is a pleiotropic cytokine that promotes host defense, cell survival and tissue regeneration under homeostatic condition However, if dysregulated and overexpressed, TNF is a major driver of chronic inflammation. Excessive TNF production in the gastrointestinal tract targets the epithelium, drives increased cell death, and is sufficient to elicit substantial tissue inflammation and chronic disease. Blockade of TNF is a widely utilized biologic that provides therapeutic benefit in a subset of inflammatory bowel disease (IBD) patients. Despite this knowledge, the mechanisms that control the beneficial versus detrimental roles of TNF in the intestine are poorly defined. The fundamental focus of this proposal is to mechanistically define a novel pathway that protects the intestine from TNF-driven damage and inflammation. In recently published and new preliminary data, we have determined that group 3 innate lymphoid cells (ILC3s) are essential to protect the intestinal epithelium from TNF-driven damage and inflammation. Surprisingly, this did not occur via traditional effector pathways, and rather involved production of prostaglandins and growth factors. These data provoke a fundamental hypothesis that ILC3s are essential to shape the protective versus pathologic roles of TNF in the intestine, and this balance is disrupted in human IBD where ILC3s are known to become dysregulated. We will mechanistically test this hypothesis by asking the following specific questions: (1) How does ILC3 production of sensing of prostaglandins impact intestinal health and inflammation? And (2) What are the cellular and molecular mechanisms by which ILC3-derived HB-EGF augments intestinal immunity and protects the gut from TNF? Finally, we will directly translate our findings from basic mouse models into samples from IBD patients. Results from these experiments will pave the way for a greater understanding of TNF-driven intestinal damage and inflammation, which could provoke novel preventative, therapeutic or curative strategies for multiple chronic inflammatory diseases.

项目摘要肿瘤坏死因子 (TNF) 是一种多效性细胞因子，可促进宿主防御、细胞存活和组织稳态条件下的再生然而，如果失调和过度表达，TNF 是主要驱动因素慢性炎症。胃肠道中过量的 TNF 生成针对上皮细胞，驱动细胞死亡增加，足以引发严重的组织炎症和慢性疾病。封锁 TNF 是一种广泛使用的生物制剂，可为炎症性肠病的一部分提供治疗益处（炎症性肠病）患者。尽管有这些知识，但控制有益与有害作用的机制肠道中的 TNF 定义不明确。该提案的根本重点是机械地定义了一种保护肠道免受 TNF 驱动的损伤和炎症的新途径。在最近发表的新初步数据，我们确定第 3 组先天淋巴细胞 (ILC3) 对于保护肠上皮免受 TNF 驱动的损伤和炎症至关重要。令人惊讶的是，这不是通过传统的效应途径发生的，而是涉及前列腺素的产生和生长因素。这些数据引发了一个基本假设，即 ILC3 对于塑造保护性与 TNF 在肠道中的病理作用，而这种平衡在人类 IBD 中被破坏，其中 ILC3 已知变得失调。我们将通过提出以下具体问题来机械地检验这一假设： (1) 前列腺素感应的 ILC3 产生如何影响肠道健康和炎症？以及 (2) ILC3 衍生的 HB-EGF 增强肠道免疫力的细胞和分子机制是什么并保护肠道免受 TNF 的侵害？最后，我们将直接将基本小鼠模型的发现转化为来自 IBD 患者的样本。这些实验的结果将为更好地理解铺平道路 TNF 驱动的肠道损伤和炎症，可能会引发新的预防、治疗或治疗方法多种慢性炎症性疾病的治疗策略。