Generation and characterization of a humanized mouse model of Crohn's disease

克罗恩病人源化小鼠模型的生成和表征

• 批准号: 10195523
• 负责人: Richard A. Flavell
• 金额: $ 8.38万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10195523
• 关键词: Affect; American; Anemia; Animal Model; Antigen-Antibody Complex; B-Lymphocytes; Blood; CD34 gene; CD4 Positive T Lymphocytes; CRISPR/Cas technology; Cells; Chemicals; Chronic; Clinic; Clinical Trials; Colitis; Colon; Communities; Complex; Crohn' s disease; Development; Disease; Distal part of ileum; Engineering; Engraftment; Environmental Risk Factor; Flow Cytometry; Future; Generations; Genes; Genetic; Genetic Engineering; Goals; Hematopoietic stem cells; Histopathology; Human; Human Genetics; Immune; Immune response; Immune system; Immunodeficient Mouse; Infiltration; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Intestines; Kinetics; Knock-in; Lamina Propria; Modeling; Molecular; Mus; Myelogenous; Natural History; Natural Killer Cells; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Physiology; Pilot Projects; Population; Preclinical Testing; Regimen; Research; Role; Small Intestines; System; T-Lymphocyte; Technology; Time; Tissues; Transcript; Translating; Ulcerative Colitis; Ursidae Family; confocal imaging; cytokine; effectiveness evaluation; genetic variant; gut microbiota; human imaging; humanized mouse; immunopathology; in vivo; insight; intraepithelial; macrophage; mouse development; mouse model; neutrophil; novel therapeutics; overexpression; pre-clinical; pre-clinical assessment; secondary lymphoid organ; side effect; therapeutic candidate; therapeutic target; tool; translational study

Generation and characterization of a humanized mouse model of Crohn’s disease Crohn’s-disease (CD) and ulcerative colitis (UC) are the two major forms of inflammatory bowel disease (IBD), a chronic inflammatory disorder that affects an estimated 3 million Americans. The etiopathogenesis of CD is distinctive for each patient and involves a complex interaction between genetic factors, the immune system, the gut microbiota and other environmental factors. Mouse models of IBD have been invaluable in providing critical mechanistic insights into its complex etiopathogenesis and in indicating new potential therapeutic targets. However, it has been particularly difficult to translate advances in our understanding of IBD pathogenesis into novel therapies that prove successful in the clinic. A major obstacle is that mice and humans, despite their similarities, have fundamental differences in their intestinal physiology and, crucially, in the function of their immune system. A second problem is that the vast majority of mouse models of IBD recapitulate aspects of the natural history of UC but not the unique pathology of CD. Not surprisingly, notable examples of clinical trials that failed in CD patients were originally guided by mouse models of colitis at the preclinical level. One inviting avenue for pre-clinical testing is humanized mouse modeling, where human hematopoietic stem cells (HSCs) are engrafted into immunodeficient mice and a human immune system develops in the mouse host. Humanized mouse models allow to study the function of human immune cells in vivo without directly involving human patients. Despite recent progress in the humanization of the immune system in mice, the development of humanized models of IBD is lagging behind and has been limited to the chemical induction of colitis upon transfer of human CD4+ T-cells. Translational animal models that faithfully recapitulate human CD pathology have been lacking. In this project we aim to develop the first humanized mouse model of CD. For this purpose we will integrate two state-of-the-art mouse models: a genetic mouse model that specifically resembles the pathological and mechanistic features of human CD and the MISTRG6 humanized model which supports the most comprehensive humanization of the immune system achieved to date, including not only T, B and NK cells, but also myeloid populations crucial in CD such as macrophages and neutrophils. Major goals of this pilot project are to 1) generate these mice by CRISPR/Cas9 engineering and optimize the humanization of their immune system and 2) determine the kinetics of humanized Crohn’s pathogenesis and thoroughly characterize its phenotypic aspects at the level of tissue pathology and intestinal immune responses. This humanized system will be an important and unique preclinical/translational tool for the CD research community. It will reveal pathways employed by human immune cells to drive CD pathogenesis and also enable future studies assessing the effectiveness of candidate therapeutics against human targets as well as studies aiming to uncover the specific effect of human genetic variants associated with CD on the function of a human immune system.

克隆氏病人源化小鼠模型的建立与表征