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.

项目总结 炎症性肠病(IBD)是当肠道微生物在肠道引起不适当的免疫反应时发生的 肠道，导致慢性炎症和组织损伤。随着全球病例的上升，重要的是要确定 抑制这些反应并促进粘膜愈合的途径。关键是，第3组先天淋巴组织 细胞(ILC3)是最近发现的一种细胞类型，它在健康的肠道中丰富，并成为 在炎症性肠病、结肠癌和其他慢性炎症性疾病期间调节失调。此外，老鼠模型有 揭示了ILC3在控制免疫耐受、免疫和炎症中的基础作用 肠子。尽管有这些进展，ILC3感知和响应错综复杂的环境的机制 肠粘膜中存在的信号可以协调肠道健康、影响炎症或促进组织 治疗仍然不清楚，这是未来研究的一个重要领域。在新的初步数据中，我有 意外地确定ILC3独特地富含细胞表面硫酸乙酰肝素的表达 蛋白多糖受体，Syndecan-4，与伤口愈合，细胞迁移/黏附和控制有关的途径 生长因子信号。此外，我还发现了一种调节ILC3s上Syndecan-4的细胞和分子机制 并发现Syndecan-4在实验性小鼠肠炎模型中变得失调 或者人类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 肠道发炎。这引发了一种新的假设，即Syndecan-4是影响ILC3的关键途径 生物学，宿主-微生物区系动态平衡，以及肠道健康和炎症期间的组织修复。这个 本研究建议的基本重点是检验这一假说，并定义调节和功能 通过采用新的小鼠模型，创新的技术方法， 和翻译研究。预计这项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 IBD的治疗。