ILC3 Syndecan-4 in the Regulation of Intestinal Health and Inflammation

ILC3 Syndecan-4 在肠道健康和炎症调节中的作用

• 批准号: 10678494
• 负责人: Brooke Elizabeth Fiedler
• 金额: $ 4.77万
• 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: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10678494
• 关键词: Address; Adhesions; Antigen Presentation; Architecture; Area; Award; Binding; Cell Adhesion; Cell Communication; Cell surface; Cells; Cellular biology; Chronic; Colon; Colon Carcinoma; Communication; Complex; Critical Pathways; Data; Data Set; Defect; Development; Diagnosis; Diet; Disease; Economic Burden; Ensure; Epithelium; FGF2 gene; Fibroblast Growth Factor; Future; Gastrointestinal tract structure; Genetic; Growth Factor; Growth Factor Receptors; Gut Mucosa; Health; Healthcare; Heparan Sulfate Proteoglycan; Homeostasis; Human; IL17 gene; IL1R1 gene; Immune; Immune Tolerance; Immune response; Immunity; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestinal Mucosa; Intestines; Investigation; Knowledge; Life Style; Link; Lymphocyte; Lymphoid Cell; Maintenance; Molecular; Mucous Membrane; Mus; Natural Immunity; Pathway interactions; Patients; Physiological; Population; Predisposition; Prevalence; Production; Regulation; Research Proposals; Role; Signal Transduction; Source; Testing; Therapeutic; Therapeutic Intervention; Tissues; Training; United States; Vascular Endothelial Growth Factors; adaptive immune response; adaptive immunity; antimicrobial; cell motility; cell type; comorbidity; cytokine; dysbiosis; gut health; gut inflammation; gut microbes; gut microbiota; healing; host microbiota; innovation; interleukin-22; intestinal barrier; intestinal epithelium; microbial; microbiota; migration; mouse model; new therapeutic target; novel; novel therapeutics; prevent; receptor; repaired; response; restraint; selective expression; single-cell RNA sequencing; socioeconomics; success; syndecan; syndecan-4; targeted treatment; tissue repair; transcription factor; translational study; wound healing

PROJECT SUMMARY Inflammatory bowel disease (IBD) arises when gut microbes elicit inappropriate immune responses in the intestine, leading to chronic inflammation and tissue damage. As cases rise worldwide, it is important to identify the pathways that restrain these responses and promote mucosal healing. Critically, group 3 innate lymphoid cells (ILC3s) are a recently identified cell type which is enriched in the healthy intestine and becomes dysregulated during IBD, colon cancer and other chronic inflammatory disorders. Further, mouse models have revealed fundamental roles for ILC3s in controlling immune tolerance, immunity, and inflammation in the intestine. Despite these advances, the mechanisms by which ILC3s sense and respond to the intricate milieu of signals present in the intestinal mucosa to coordinate intestinal health, impact inflammation, or promote tissue healing remains unclear and represents an important area of future investigation. In new preliminary data, I have unexpectedly determined that ILC3s are uniquely enriched in expression of a cell surface heparan sulfate proteoglycan receptor, syndecan-4, a pathway linked to wound healing, cell migration/adhesion, and control of growth factor signaling. Further, I identified a cellular and molecular mechanism regulating syndecan-4 on ILC3s and discovered that syndecan-4 becomes dysregulated in experimental mouse models of intestinal inflammation or human IBD. Finally, mice lacking ILC3-specific syndecan-4 show greater tissue damage and susceptibility to intestinal inflammation. This provokes a novel hypothesis that syndecan-4 is a critical pathway impacting ILC3 biology, host-microbiota homeostasis, and tissue repair during intestinal health and inflammation. The fundamental focus of this research proposal is to test this hypothesis and define the regulation and functional significance of ILC3-specific syndecan-4 by employing novel mouse models, innovative technical approaches, and translational studies. It is expected that the results from the two aims of this proposal will reveal crucial signaling mechanisms for inflammatory responses in the intestine that may have therapeutic potential for the treatment of IBD.

项目概要 当肠道微生物在肠道中引起不适当的免疫反应时，就会出现炎症性肠病（IBD）。 肠道，导致慢性炎症和组织损伤。随着全球病例的增加，重要的是要确定 抑制这些反应并促进粘膜愈合的途径。至关重要的是，第 3 组先天淋巴 细胞（ILC3）是最近发现的一种细胞类型，它在健康肠道中富集并成为 IBD、结肠癌和其他慢性炎症性疾病期间失调。此外，小鼠模型具有 揭示了 ILC3 在控制免疫耐受、免疫和炎症方面的基本作用 肠。尽管取得了这些进展，ILC3 感知和响应复杂环境的机制仍然存在。 肠粘膜中存在的信号可协调肠道健康、影响炎症或促进组织 愈合情况仍不清楚，是未来研究的一个重要领域。在新的初步数据中，我有 出乎意料地确定ILC3在细胞表面硫酸乙酰肝素的表达中独特地富集 蛋白聚糖受体 Syndecan-4，与伤口愈合、细胞迁移/粘附和控制相关的途径 生长因子信号传导。此外，我还确定了 ILC3 上调节 syndecan-4 的细胞和分子机制 并发现 syndecan-4 在肠道炎症实验小鼠模型中失调 或人类 IBD。最后，缺乏 ILC3 特异性 syndecan-4 的小鼠表现出更大的组织损伤和对 肠道炎症。这引发了一个新的假设，即 syndecan-4 是影响 ILC3 的关键途径 肠道健康和炎症期间的生物学、宿主微生物群稳态和组织修复。这 本研究提案的基本重点是检验这一假设并定义监管和功能 通过采用新型小鼠模型、创新技术方法来了解 ILC3 特异性 syndecan-4 的重要性， 和转化研究。预计该提案的两个目标的结果将揭示至关重要的 肠道炎症反应的信号机制可能具有治疗潜力 治疗炎症性肠病。