Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Center for Computational and Integrative Biology and Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Dev Cell. 2024 Sep 23;59(18):2460-2476.e10. doi: 10.1016/j.devcel.2024.06.001. Epub 2024 Jun 27.
Recent advances in human genetics have shed light on the genetic factors contributing to inflammatory diseases, particularly Crohn's disease (CD), a prominent form of inflammatory bowel disease. Certain risk genes associated with CD directly influence cytokine biology and cell-specific communication networks. Current CD therapies primarily rely on anti-inflammatory drugs, which are inconsistently effective and lack strategies for promoting epithelial restoration and mucosal balance. To understand CD's underlying mechanisms, we investigated the link between CD and the FGFR1OP gene, which encodes a centrosome protein. FGFR1OP deletion in mouse intestinal epithelial cells disrupted crypt architecture, resulting in crypt loss, inflammation, and fatality. FGFR1OP insufficiency hindered epithelial resilience during colitis. FGFR1OP was crucial for preserving non-muscle myosin II activity, ensuring the integrity of the actomyosin cytoskeleton and crypt cell adhesion. This role of FGFR1OP suggests that its deficiency in genetically predisposed individuals may reduce epithelial renewal capacity, heightening susceptibility to inflammation and disease.
近年来，人类遗传学的进展揭示了导致炎症性疾病的遗传因素，特别是克罗恩病（CD），这是一种主要的炎症性肠病形式。某些与 CD 相关的风险基因直接影响细胞因子生物学和细胞特异性通讯网络。目前的 CD 治疗主要依赖于抗炎药物，但这些药物的效果不一致，缺乏促进上皮修复和黏膜平衡的策略。为了了解 CD 的潜在机制，我们研究了 CD 与 FGFR1OP 基因之间的联系，该基因编码一种中心体蛋白。在小鼠肠上皮细胞中缺失 FGFR1OP 会破坏隐窝结构，导致隐窝丢失、炎症和死亡。FGFR1OP 不足会阻碍结肠炎期间上皮的恢复能力。FGFR1OP 对于维持非肌肉肌球蛋白 II 的活性至关重要，确保肌动球蛋白细胞骨架和隐窝细胞黏附的完整性。FGFR1OP 的这种作用表明，在遗传易感性个体中其缺失可能会降低上皮更新能力，增加炎症和疾病的易感性。
