Genetic Models Core
|Cornelis Terhorst, Ph.D.
|Hans-Christian Reinecker, M.D.
Atul Bhan, M.D.
Robert Sedlacek, M.Sc.
|Steven Niemi, D.V.M, Ph.D.
Crohn’s disease (CD) and ulcerative colitis (UC) are diseases of the gastrointestinal tract, collectively known as the inflammatory bowel diseases (IBD). Recent efforts in genome-wide association studies (GWAS) identified 30 genes associated with CD, e.g., CARD15, IL-23R, ATG16L1, TNFSF15 and IRGM. These studies have highlighted the significance of the relationship between intracellular responses to microbes (autophagy, phagocytosis and innate immunity) and regulation of adaptive immunity (IL-23 ==> Th17 cells) in the pathogenesis of IBD. Spontaneous gene mutations, targeted disruption and transgenic expression of selected mouse genes have unveiled a number of additional adaptive and innate immune genes that govern the pathogenesis of chronic enterocolitis. Thus, both approaches have proven to be of importance toward understanding the molecular underpinnings of these complex diseases.
Rodent models of chronic intestinal inflammation provide useful tools to dissect the pathways that lead to pathogenesis of IBD. Targeted disruption or transgenic expression of genes, manipulation of selected lymphocyte subsets and spontaneous gene mutations demonstrate that immunoregulatory abnormalities lead to chronic intestinal and systemic inflammation.
- Breeding and maintenance of mutant mouse stocks
- Characterization of murine models
- Sample collection from murine models of IBD
- New murine model development
- Bone marrow transfers and adoptive T cell transfers
- Maintenance of GFP- and RFP- reporter mice
- In vivo tracking of fluorescently labeled bacteria and cells
- Mouse bright field and fluorescent endoscopy
- Whole body imaging of bioluminescent and fluorescent signals
- Spontaneous chronic colitis in mutant mice, e.g., IL-10-/- and TCR-α-/-
- Colitis induced by adoptive transfers of wt or mutant T cell subsets into:
- CD4+ CD45Rbhi transfer into immuno-deficient mice (RAG-/-).
- Double or triple mutant mice derived by genetic crosses between Rag-/- and mutant mice
- Anti-CD40 induced colitis in Rag-/- mice or into double or triple knockout mice derived by genetic crosses between RAG-/- and mutant mice that are impaired in innate immune responses
- Colitis induced by bone marrow transplantation into tge26 immuno-deficient mice; followed by adoptive transfers of mesenteric lymph node derived CD4+ T cells into tgε26 or Rag-/- mice
- Chemically induced colitis in mutant mice, e.g., DSS or TNBS
- Isolation and functional characterization of lamina propria and intestinal epithelial lymphocyte subsets, dendritic cell subsets and macrophages isolated from wild type and mutant mice with or without disease
- Gnotobiotic Mouse facilities
- Mouse models for functional imaging of the mucosal immune system