The current data in the literature provide conflicting results on the association of human Toll-like receptor 4 (TLR4) single nucleotide polymorphisms (SNP) and a variety of diseases, including sepsis, meningococcal disease, cerebral malaria, Crohn's disease, ulcerative colitis, respiratory syncytial virus, atherosclerosis, rheumatoid arthritis, malignant melanoma, and metabolic syndrome. Analysis of the role of human TLR4 SNPs in these diverse diseases has been hampered by the lack of a suitable animal model. We have recently developed a new transgenic mouse model that encodes human rather than mouse TLR4 as well as its coreceptor MD-2. This new transgenic line displays more human-like responses to Gram-negative bacterial infections than conventional mice. In this R21 grant application, we propose to extend our studies to newly generated lines expressing the most common human TLR4 variants, namely TLR4D299G and TLR4D299G+T399I. Results obtained here will determine whether these novel TLR4 SNP mice could be of benefit for the study of the large range of infectious and non-infectious diseases where TLR4 SNP associations have been described.

Public Health Relevance

This project aims to refine and improve newly developed transgenic mouse models that mimic human responses mediated through Toll-like receptor 4 (TLR4). If successful, it will be possible to address the role of TLR4 single nucleotide polymorphisms in a variety of infectious and non-infectious diseases by directly comparing mice that differ only in the sequence of human TLR4.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21OD017233-01A1
Application #
8701498
Study Section
Immunity and Host Defense (IHD)
Program Officer
Mirochnitchenko, Oleg
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Washington
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98195