Tissue destruction and healing in Celiac Disease

乳糜泻的组织破坏和愈合

• 批准号: 10518839
• 负责人: Luis Bruno Barreiro
• 金额: $ 242.63万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518839
• 关键词: Activities of Daily Living; Address; Adult; Affect; Autoimmune; Biochemical; Biological; Bone Diseases; Celiac Disease; Cells; Cellular biology; Chemistry; Child; Childhood; Cholesterol; Clinical; Clinical Research; Communities; Complex; Consumption; Data; Data Analyses; Data Set; Defect; Development; Diet; Digestive System Disorders; Disease; Duodenum; Epithelial; Epithelial Cells; Family member; Genetic; Gluten; Gluten-free diet; Guide prevention; HLA-DQ2; HLA-DQ8 antigen; Health; Heterogeneity; Human; Immune; Immune system; Immunity; Immunologics; Immunology; Individual; Inflammatory; Informatics; Information Resources; Institution; Interferon Type II; International; Intervention; Intestinal Mucosa; Intestines; Investigation; Iron; Knowledge; Link; Lipids; Lymphoma; Malignant Neoplasms; Mediating; Medical; Metabolic; Metadata; Metagenomics; Mission; Molecular; Monitor; Mucous Membrane; National Institute of Diabetes and Digestive and Kidney Diseases; Nutrient; Organoids; Pathogenesis; Patient Care; Patients; Population; Preventive; Process; Publications; Research; Resources; Role; Sampling; Science; Severities; Small Intestines; Small intestine mucous membrane; Symptoms; T-Lymphocyte; Testing; Tissue Model; Tissues; Villous Atrophy; Vitamins; Work; base; biobank; cell type; clinical care; clinical heterogeneity; clinical phenotype; cohort; data management; dietary; follow-up; gene expression variation; healing; human disease; improved; intestinal epithelium; knowledge base; metabolic phenotype; metabolomics; microbial; microbiome; microbiota; mucosal microbiota; multiple omics; non-invasive monitor; novel therapeutic intervention; novel therapeutics; pediatric patients; personalized approach; personalized care; precision medicine; precision medicine clinical trials; predictive modeling; tool; treatment choice; user-friendly; web platform

PROJECT SUMMARY Celiac disease (CeD) is a complex T cell-mediated enteropathy induced by dietary gluten in HLA-DQ2+ and/or HLA-DQ8+ individuals, which currently affects 1% of the global population. A gluten-free diet (GFD) is, to this date, the treatment of choice for CeD. However, 50% of CeD patients are unable to effectively adhere to a diet that sustainably excludes gluten, with many patients suffering from inadvertent gluten exposure. Moreover, over 30% of CeD patients have persistent high symptom burdens, resulting from continued mucosal damage, despite adhering to a GFD. Persistent mucosal damage on a GFD is associated with several severe complications, including malignancies, especially lymphomas and bone diseases. In addition, patients with active CeD display a wide range of clinical presentations, including metabolic defects (vitamins, iron, and cholesterol) that are not correlated to the degree of tissue damage. Although much progress has been made in understanding CeD, major gaps remain, notably regarding the biological mechanisms involved in different clinical presentations and the inconsistent healing process. For instance, it is poorly understood why, independently from the degree of villous atrophy, certain patients display nutrient and lipid deficiencies, whereas others have normal levels of vitamins, cholesterol, and iron. Furthermore, while there is evidence for a role of the microbiome in CeD, we lack information on small-intestinal mucosal microbiota in human CeD (which is more likely to have metabolic effects and directly interact with the immune system). Finally, we have little knowledge about interactions between gluten, intestinal epithelial cells (IECs), immune cells, and the microbiota, and how they are linked to the different CeD clinical phenotypes. Our RC2 proposal will test the hypothesis that CeD is a heterogeneous disorder, while attempting to define interactions between IECs, microbiota, immune system, and genetics that underlie differences in clinical presentation, severity of tissue destruction, and the ability to heal. It will also address critical gaps in our understanding of CeD pathogenesis and clinical presentations, and develop tools for non-invasive monitoring of CeD patients. We have assembled a team of internationally recognized experts in the field of CeD, epithelial cell biology, mucosal immunology, microbiome, and chemistry. The RC2 proposal is anchored around multi-omics studies performed in the context of cross-sectional and interventional gluten challenge and de-challenge studies, on 445 well-characterized adult and pediatric patients. The proposed specific aims are: 1) Developing an approach to precision medicine in CeD; 2) Deciphering the mechanisms associated with tissue destruction and healing in CeD, 3) Developing non-invasive tools for monitoring CeD patients, and 4) Developing research resources for the scientific and medical community to advance patient care as well as discovery-based and hypothesis-generating science. This application aims to generate the much- needed knowledge base and resources to further our understanding of CeD pathogenesis and its heterogeneity, improve individualized patient care and follow-up, and develop new therapeutic and preventive targets.

项目概要 乳糜泻 (CeD) 是一种复杂的 T 细胞介导的肠病，由 HLA-DQ2+ 和/或 HLA-DQ2+ 中的膳食麸质诱导 HLA-DQ8+ 个体，目前影响全球人口的 1%。无麸质饮食（GFD）对此 迄今为止，CeD 的首选治疗方法。然而，50% 的 CeD 患者无法有效坚持饮食 这持续地排除了麸质，导致许多患者无意中接触到麸质。而且，超过 30% 的 CeD 患者由于持续的粘膜损伤而持续存在高症状负担，尽管 遵守 GFD。 GFD 的持续粘膜损伤与多种严重并发症有关， 包括恶性肿瘤，特别是淋巴瘤和骨病。此外，具有主动 CeD 显示的患者 广泛的临床表现，包括代谢缺陷（维生素、铁和胆固醇） 与组织损伤程度相关。尽管在理解 CeD 方面已经取得了很大进展， 仍然存在重大差距，特别是在不同临床表现和涉及的生物学机制方面 不一致的愈合过程。例如，人们很少理解为什么，与程度无关 绒毛萎缩，某些患者表现出营养和脂质缺乏，而其他患者的营养和脂质水平正常 维生素、胆固醇和铁。此外，虽然有证据表明微生物组在 CeD 中发挥作用，但我们缺乏 人类 CeD 中小肠粘膜微生物群的信息（更有可能具有代谢影响 并直接与免疫系统相互作用）。最后，我们对麸质之间的相互作用知之甚少， 肠上皮细胞 (IEC)、免疫细胞和微生物群，以及它们如何与不同的 CeD 联系起来 临床表型。我们的 RC2 提案将检验 CeD 是一种异质性疾病的假设，而 试图定义 IEC、微生物群、免疫系统和遗传学之间的相互作用 临床表现、组织破坏的严重程度和愈合能力存在差异。它还将 解决我们对 CeD 发病机制和临床表现理解中的关键差距，并开发 对 CeD 患者进行无创监测的工具。我们组建了一支国际公认的团队 CeD、上皮细胞生物学、粘膜免疫学、微生物组和化学领域的专家。 RC2 提案以在横断面和介入背景下进行的多组学研究为基础 对 445 名特征明确的成人和儿童患者进行的麸质挑战和去挑战研究。拟议的 具体目标是： 1) 开发 CeD 精准医学方法； 2）破译机制 与 CeD 中的组织破坏和愈合相关，3) 开发用于监测 CeD 的非侵入性工具 患者，以及 4) 为科学界和医学界开发研究资源以促进患者护理 以及基于发现和假设生成的科学。该应用程序旨在生成更多 需要知识库和资源来进一步了解 CeD 发病机制及其异质性， 改善个体化患者护理和随访，并制定新的治疗和预防目标。