Mechanisms of TL1A-driven Paneth Cell dysfunction in IBD

IBD 中 TL1A 驱动的潘氏细胞功能障碍的机制

• 批准号: 10539302
• 负责人: Stephan R. Targan
• 金额: $ 38.25万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10539302
• 关键词: Abnormal Cell; Address; Affect; American; Antigen-Antibody Complex; Area; Automobile Driving; Autophagocytosis; Bacteria; Bacterial Antibodies; Binding; Biological Models; Biological Products; Cell Differentiation process; Cell Maturation; Cell physiology; Cells; Cellular Morphology; Cellular biology; Chronic; Clinical; Combined Modality Therapy; Complement; Complex; Crohn' s disease; Cytoplasmic Granules; Data; Defect; Development; Diffusion; Digestive System Disorders; Disease; Disease susceptibility; Engineering; Environment; Epithelial Cells; Etiology; Family member; Functional disorder; Gastrointestinal Diseases; Gene Deletion; Genes; Genetic Predisposition to Disease; Genetic Risk; Growth Factor; Human; Ileitis; Immune response; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Innate Immune Response; Intestines; Investigation; Link; Microbe; Modeling; Molecular; Morphology; Mucous Membrane; Muramidase; Mus; Operative Surgical Procedures; Organoids; Paneth Cells; Pathogenesis; Pathway interactions; Patients; Peripheral; Phenocopy; Phenotype; Play; Predisposition; Process; Proteins; Recurrent disease; Reporting; Resected; Role; Serum; Severities; Severity of illness; Signal Transduction; Small Intestines; Structure; Structure of intestinal gland; System; TNFSF15 gene; Testing; Therapeutic; Translating; Wild Type Mouse; Work; adaptive immune response; antimicrobial; base; commensal bacteria; commensal microbes; cytokine; disorder prevention; early onset; gut inflammation; human model; human stem cells; in vivo; induced pluripotent stem cell; intestinal homeostasis; lymphoblastoid cell line; microbial; microbial host; microbiota; microorganism; monocyte; mouse model; novel; organ on a chip; overexpression; preempt; prevent; protein expression; repository; response; risk variant; service member; small bowel Crohn' s disease; stem cells; translational study

PROJECT SUMMARY ABSTRACT Inflammatory bowel diseases (IBD) are chronic relapsing diseases of the gastrointestinal tract believed to be the result of complex interactions between genetic susceptibility and severity genes, the microbial environment, and a dysregulated innate and adaptive immune response against commensal micro-organisms. Paneth cells (PC) are specialized small bowel (SB) epithelial cells that constitutively produce anti-microbial proteins and are important in intestinal homeostasis. Abnormal PC morphology is observed in patients with Crohn’s disease (CD) and in mice with gene deletions in autophagy and unfolded protein response (UPR) pathways. Mice with PC-specific deletions in UPR and autophagy pathways develop early and severe SB inflammation. PC morphologic abnormalities precede onset of ileitis, implicating altered PC biology as central to the pathogenesis and severity of SB CD; yet the cell-extrinsic signals driving these abnormalities are undefined. TNFSF15/(TL1A) is an IBD susceptibility and severity locus and we have previously reported the relationship of a TNFSF15 risk genotype and increased expression of TL1A in peripheral monocytes and in non- inflamed SB CD. In translational studies, we also reported the association between this risk genotype and severe forms of SB CD including fibrostenosis that was phenocopied in mice overexpressing TL1A. We have found a significant association between TL1A and abnormal PC morphology. Commensal microbiota are required in TL1A-overexpressing mice to induce ileal inflammation and in wild type mice to induce normal PC maturation and expansion. We developed a novel stem cell micro-engineered chip model of functional human PC, we showed TL1A directly alters the PC phenotype by inducing diffused and disordered lysozyme granule morphology recapitulating the abnormal PC phenotypes in SB CD with high mucosal expression of TL1A. Evidence that serum levels of IBD-associated anti-bacterial antibodies are elevated in unaffected family members of patients with IBD and also in members of the military prior to clinical evidence of disease suggests defects in the host-bacterial interface precedes onset of IBD. Loss of response to biologics and disease recurrence may represent elimination of a disease driving cytokine but not the underlying process. If pre- inflammatory PC abnormality can be mitigated/prevented by manipulation of TL1A, which, addresses the microbial-host interface, potentially PC function will reset and IBD may be pre-empted in genetically susceptible individuals, and the combination may also prevent loss of response to existing therapeutics or disease recurrence. The foregoing provides a strong rationale for studying the mechanisms of TL1A-driven changes in PC morphology, maturation, and function in promoting SB inflammation, using our novel murine in vivo and human stem cell in vitro systems that allow for parallel investigations to parse out cellular and molecular interactions simultaneously. Our investigations will reveal additional downstream pathways and molecules and potentially targets for combination therapy.

项目概要摘要 炎症性肠病（IBD）是胃肠道的慢性复发性疾病，被认为是 遗传易感性和严重性基因、微生物环境之间复杂相互作用的结果， 针对共生微生物的先天性和适应性免疫反应失调。 (PC) 是专门的小肠 (SB) 上皮细胞，其组成型产生抗微生物蛋白，并且 在克罗恩病患者中观察到 PC 形态异常。 （CD）以及自噬和未折叠蛋白反应（UPR）途径基​​因缺失的小鼠。 UPR 和自噬途径中 PC 特异性缺失会导致早期和严重的 SB 炎症。 形态学异常先于回肠炎发生，表明 PC 生物学是回肠炎的核心 SB CD 的发病机制和严重程度；但驱动这些异常的细胞外在信号尚不清楚。 TNFSF15/(TL1A) 是 IBD 易感性和严重程度基因座，我们之前已报道过这种关系 TNFSF15 风险基因型以及外周单核细胞和非淋巴细胞中 TL1A 表达增加 在转化研究中，我们还报道了该风险基因型与炎症性 SB CD 之间的关联。 我们已经在过表达 TL1A 的小鼠中发现了严重形式的 SB CD，包括纤维狭窄。 发现 TL1A 与异常的 PC 共生微生物群之间存在显着关联。 TL1A 过表达小鼠诱导回肠炎症所需，野生型小鼠诱导正常 PC 我们开发了一种新型功能性人体干细胞微工程芯片模型。 PC，我们证明TL1A通过诱导扩散和无序的溶菌酶颗粒直接改变PC表型 形态学再现了 SB CD 中 TL1A 粘膜高表达的异常 PC 表型。 有证据表明，未受影响的家庭中 IBD 相关抗细菌抗体的血清水平升高 IBD 患者以及在疾病临床证据表明之前的军人中 宿主-细菌界面的缺陷先于 IBD 的发生，对生物制剂和疾病失去反应。 复发可能代表驱动细胞因子的疾病的消除，但不是潜在过程的消除。 炎症性PC异常可以通过操纵TL1A来减轻/预防，它解决了 微生物-宿主界面，潜在的 PC 功能将重置，IBD 可能在遗传上被先发制人 易感个体，并且该组合还可以防止对现有疗法或药物失去反应 上述内容为研究 TL1A 驱动的机制提供了强有力的理由。 使用我们的新型小鼠在促进 SB 炎症中 PC 形态、成熟和功能的变化 体内和人类干细胞体外系统，允许并行研究以解析细胞和 我们的研究将同时揭示其他下游途径和 分子和联合治疗的潜在靶点。