Novel mechanisms protecting the gut from TNF

保护肠道免受 TNF 侵害的新机制

• 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
• 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

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）是一种多效细胞因子，可促进宿主防御、细胞存活和组织 然而，如果失调和过度表达，TNF是一个主要的驱动因素， 慢性炎症胃肠道中过量的TNF产生靶向上皮细胞， 增加的细胞死亡，并足以引起实质性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 (IBD)患者尽管有这些知识，但控制蛋白质的有益作用和有害作用的机制仍然是未知的。 肠道中的TNF定义不明确。这项建议的基本重点是从机制上 定义了一种新的途径，保护肠道免受TNF驱动的损伤和炎症。在 最近发表的新的初步数据，我们已经确定，第3组先天淋巴细胞（ILC 3） 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 并不通过传统的效应途径发生，而是涉及到拟南芥素的产生和生长 因素这些数据引发了一个基本假设，即ILC 3对形成保护性与 TNF在肠道中的病理作用，这种平衡在人IBD中被破坏，其中已知ILC 3 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)ILC 3如何产生对胰高血糖素的感知，从而影响肠道健康和炎症？（2） ILC 3衍生的HB-EGF增强肠道免疫的细胞和分子机制是什么 并保护肠道免受肿瘤坏死因子的侵害？最后，我们将直接将我们的发现从基本的小鼠模型转化为 来自IBD患者的样本。这些实验的结果将为更好地理解 肿瘤坏死因子驱动的肠道损伤和炎症，这可能会引发新的预防，治疗或 多种慢性炎症性疾病的治疗策略。