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

项目摘要 炎症性肠病（IBD）是由肠道微生物引起肠道内不适当的免疫反应引起的。 肠道，导致慢性炎症和组织损伤。随着全球病例的增加， 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 细胞（ILC 3）是最近鉴定的细胞类型，其在健康肠中富集， 在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ILC 3在控制免疫耐受、免疫和炎症中的基本作用。 肠子尽管取得了这些进展，但ILC 3感知和应对复杂环境的机制仍然存在一些问题。 存在于肠粘膜中的信号，以协调肠道健康，影响炎症或促进组织 愈合仍然不清楚，代表了未来研究的重要领域。在新的初步数据中， 出乎意料地确定ILC 3独特地富集细胞表面硫酸乙酰肝素的表达 蛋白聚糖受体，syndecan-4，与伤口愈合，细胞迁移/粘附和控制 生长因子信号传导此外，我确定了调控ILC 3上syndecan-4的细胞和分子机制。 并发现syndecan-4在实验性小鼠肠道炎症模型中变得失调 或人IBD。最后，缺乏ILC 3特异性syndecan-4的小鼠表现出更大的组织损伤和对ILC 3的易感性。 肠道炎症这引发了一个新的假设，即syndecan-4是影响ILC 3的关键途径 生物学、宿主微生物群稳态和肠道健康和炎症期间的组织修复。的 这项研究的基本重点是测试这一假设，并确定调节和功能 ILC 3特异性多配体蛋白聚糖-4的重要性，通过采用新的小鼠模型，创新的技术方法， 和翻译研究。预计这一建议的两个目标的结果将揭示关键的 肠道炎症反应的信号传导机制，可能具有治疗潜力 IBD的治疗

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.