Preclinical services

The Nutritional Immunology and Molecular Medicine Laboratory offers a broad array of preclinical services in mouse, rats, hamsters and pigs for product testing, mechanism of action validation studies, and hypothesis–driven and hypothesis-generating in vivo experimentation. All our preclinical animal models are set up in Virginia Tech animal facilities and are approved by the Virginia Tech Institutional Animal Care and Use Committee (IACUC). The mice are housed in a state-of-art facility that can accommodate large projects as well as both animal biosafety level (ABL)-1 and ABL-2 experiments. These services will be provided as a part of a sponsored research agreement with Virginia Tech.

1. Preclinical models for Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) is characterized by two major clinical manifestations: Crohn’s disease (CD) and ulcerative colitis (UC). CD can affect any regions of the gastrointestinal (GI) tract from mouth to anus. In contrast, UC causes acute colonic inflammation.

The NIMML offers expertise and services in mouse models of IBD such as trinitrobenzene sulfonic acid (TNBS), dextran sodium sulfate (DSS)-induced colitis, pan-enteritis due to the deficiency of interleukin-10 (IL-10 KO) and CD4+ T cell-induced colitis in adoptive transfer models. Whereas TNBS and DSS-induced colitis represent the more acute and faster induction of colonic tissue damage, the IL-10 KO and the CD4+ T cell induced colitis represent chronic models of IBD. We have also developed a model of inflammation-driven colorectal cancer (CRC) following treatment of mice with azoxymethane and DSS.

The NIMML provides expertise and resources in these four preclinical models with more than 10 years of experience and results published in top gastroenterology journals.

Selected References:

1. Activation of PPAR gamma and delta by conjugated linoleic acid mediates protection from experimental inflammatory bowel disease Bassaganya-Riera J, Reynolds K, Martino-Catt S, Cui Y, Hennighausen L, Gonzalez F, Rohrer J, Benninghoff AU, Hontecillas R. Gastroenterology. 2004 Sep;127(3):777-91.

2. Peroxisome proliferator-activated receptor gamma is required for regulatory CD4+ T cell-mediated protection against colitis Hontecillas R, Bassaganya-Riera J. J Immunol. 2007 Mar 1;178(5):2940-9.

3. T cell PPARγ is required for the anti-inflammatory efficacy of abscisic acid against experimental IBD. Guri AJ, Evans NP, Hontecillas R, Bassaganya-Riera J. J Nutr Biochem. 2011 Sep;22(9):812-9. Epub 2010 Dec 15.

4. Immunoregulatory actions of epithelial cell PPAR gamma at the colonic mucosa of mice with experimental inflammatory bowel disease. Mohapatra SK, Guri AJ, Climent M, Vives C, Carbo A, Horne WT, Hontecillas R, Bassaganya-Riera J. PLoS One. 2010 Apr 20;5(4):e10215.

5. Immunoregulatory mechanisms of macrophage PPAR-γ in mice with experimental inflammatory bowel disease. Hontecillas R, Horne WT, Climent M, Guri AJ, Evans C, Zhang Y, Sobral BW, Bassaganya-Riera J. Mucosal Immunol. 2011 May;4(3):304-13. Epub 2010 Nov 10.

6. The role of T cell PPAR gamma in mice with experimental inflammatory bowel disease. Guri AJ, Mohapatra SK, Horne WT 2nd, Hontecillas R, Bassaganya-Riera J. BMC Gastroenterol. 2010 Jun 10;10:60.

7. Dietary α-eleostearic acid ameliorates experimental inflammatory bowel disease in mice by activating peroxisome proliferator-activated receptor-γ. Lewis SN, Brannan L, Guri AJ, Lu P, Hontecillas R, Bassaganya-Riera J, Bevan DR. PLoS One. 2011;6(8):e24031. Epub 2011 Aug 31.

NIMML can provide data on

  • Immunological changes at the gut mucosa and systemically
  • Gut histological and immunohistochemical changes
  • Transcriptomic analyses (RNAseq, ChipSep, miRNA)
  • Pre-clinical efficacy, tolerability and weight loss
  • Cellular and molecular profiling

2. Preclinical models for Infectious diseases: Respiratory pathogens

The NIMML has been working on Influenza models with several strains, being able to develop lung damage (i.e., epithelial necrosis, leucocyte infiltration), weight loss 10-20% and clinical disease. The virus strains we are using in mouse and pig challenge studies include:

  • H1N1 strain A/Puerto Rico/8/34 (PR8)
  • H3N2 strain A/Udorn/72
  • H1N1 strain A/California/07/2009

NIMML can provide data on:

  • Viral disease progression, weight loss
  • Histology and immunohistochemistry
  • Vaccine and therapeutic efficacy
  • Immunological assays and flow cytometry
  • Viral titers
  • LD50 studies

3. Preclinical models of Infectious diseases: Gastrointestinal pathogens

Yearly outbreaks of several pathotypes of E. coli, Salmonella, and other enteric pathogens incur medical costs, lost productivity and even premature death, with total expenses exceeding $6.9 billion per year. A closer comprehension of the mechanisms of action underlying immune responses to enteric pathogens will lead to the development of more efficacious vaccines and immunotherapeutics. Through the Modeling Immunity to Enteric Pathogens program, NIMML has build capabilities in modeling gut enteric infections.

NIMML can reproduce and validate the following infectious disease models:

  • Enteroaggregative Escherichia coli(EAEC)
    • JM221 strain
    • 042 strain
  • Helicobacter pylori
    • European 26695 strain
    • African J99 strain
    • SS1 strain
  • Clostridium difficile
    • UVA13 strain
    • VPI 11186 strain
    • 10463 strain

4. Preclinical models to validate computational model approaches

The NIMML works in the interface between the experimental and modeling/simulation approaches to study the host responses to gut and respiratory pathogens.

The modeling process requires strong crosstalk with the experimental side: model calibration and validation. Each model needs to be calibrated with experimental data to ensure correct fitting and the correct assignment on numerical values for the parameters in differential equations. Afterwards, when the model is fully calibrated with experimental data, a new window to experimental design is opened: model validation. Resulting in model-aided, hypothesis-driven experimental validation, positioning computational modeling as a effective and advanced tool for immunology research and discovery.

The NIMML has expertise in developing new designs depending on the needs of the customer. We are currently working in several validation studies for mathematical models under the MIEP program and we are flexible to design new models with creation of knockouts with the zinc finger technology. This validation approach will accelerate the whole process into a final publication, showing how computational method can validate biological processes.

 

 

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