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: 10077845
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10077845
• 关键词: Abnormal Cell; Address; Affect; American; Antigen-Antibody Complex; Area; Automobile Driving; Autophagocytosis; Bacteria; Bacterial Antibodies; Binding; Biological; Biological Models; 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; Diffuse; Digestive System Disorders; Disease; Disease susceptibility; Engineering; Environment; Epithelial Cells; Etiology; Family member; Functional disorder; Gene Deletion; Genes; Genetic Predisposition to Disease; Genetic Risk; Growth Factor; Human; Ileitis; Immune response; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestines; Investigation; Lead; Link; Microbe; Modeling; Molecular; Morphology; Mucous Membrane; Muramidase; Mus; Operative Surgical Procedures; Organoids; Paneth Cells; Pathogenesis; Pathway interactions; Patients; Peripheral; Phenocopy; Phenotype; Play; Pluripotent Stem Cells; Predisposition; Process; Proteins; Recurrence; Recurrent disease; Reporting; Resected; Role; Seeds; 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; human model; human stem cells; in vivo; intestinal homeostasis; lymphoblastoid cell line; microbial; microbial host; microbiota; microorganism; monocyte; mouse model; novel; organ on a chip; overexpression; 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， 以及针对肠道微生物的先天性和适应性免疫应答失调。潘氏细胞 (PC)是特化的小肠（SB）上皮细胞，其组成性地产生抗微生物蛋白， 对肠道内环境稳定很重要。克罗恩病患者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。小鼠 UPR和自噬途径中的PC特异性缺失会导致早期和严重的SB炎症。PC 形态学异常先于回肠炎发作，暗示PC生物学改变是回肠炎的核心。 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明确。 TNFSF 15/（TL 1A）是IBD易感性和严重程度的基因座，我们之前已经报道了这种关系 TNFSF 15风险基因型和TL 1A在外周血单核细胞和非单核细胞中的表达增加。 SB CD发炎。在翻译研究中，我们也报道了这种风险基因型与 严重形式的SB CD，包括在过表达TL 1A的小鼠中表现出的纤维狭窄。我们有 发现TL 1A和异常PC形态之间存在显著关联。共生菌群 在TL 1A过表达小鼠中诱导回肠炎症和在野生型小鼠中诱导正常PC 成熟和扩张。我们开发了一种新的干细胞微工程芯片模型， 结果表明，TL 1A通过诱导溶菌酶颗粒的分散和无序，直接改变PC的表型 形态学重现了具有TL 1A高粘膜表达的SB CD中的异常PC表型。 IBD相关抗细菌抗体的血清水平在未受影响的家族中升高的证据 IBD患者的成员以及军队成员在疾病的临床证据表明， 宿主-细菌界面的缺陷先于IBD发作。对生物制剂和疾病失去反应 复发可能代表疾病驱动细胞因子的消除，而不是潜在过程。如果预- 炎症性PC异常可以通过TL 1A的操作来减轻/预防，TL 1A解决了 微生物-主机接口，PC功能可能会重置，并且IBD可能会在基因上被抢占 该组合还可以防止对现有治疗剂的反应丧失， 疾病复发。上述内容为研究TL 1A驱动的细胞凋亡的机制提供了强有力的理论基础。 PC形态、成熟和促进SB炎症的功能的变化，使用我们的新的小鼠模型， 体内和人干细胞体外系统，允许并行研究，以解析出细胞和 分子间的相互作用。我们的研究将揭示更多的下游途径， 分子和联合治疗的潜在靶点。