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Dissertation
Analysis of the high nitric oxide and high eosinophil phenotypes in the brown Norway rat
Doctor of Philosophy (Ph.D.), Allegheny University of the Health Sciences
Sep 1997
DOI:
https://doi.org/10.17918/00009224
Abstract
Lewis (LEW) and Brown Norway (BN) rats are used as animal models for human diseases such as multiple sclerosis and metal ion-induced autoimmunity. In vitro studies conducted with these rat strains showed that (1) BN splenic T cells have a low proliferation response to superantigens and mitogens compared to LEW splenic T cells and (2) the low T cell proliferation phenotype in the BN splenic cultures correlates with the ability of the BN splenic macrophages to produce uniquely high levels of nitric oxide. The regulation of high nitric oxide levels, and the genetic basis for this regulation, are questions addressed in my dissertation project. I have determined that the high nitric oxide production in purified BN macrophage cultures corresponds to higher levels of mRNA for the inducible nitric oxide synthase (iNOS) and that stability of the iNOS mRNA is similar for LEW and BN. Microsatellite analysis conducted on (LEWxBN)xBN backcross rats allowed me to (1) map three loci on chromosomes 8, 19 and 20 that influence the high nitric oxide phenotype and (2) determine that this phenotype is not linked to the structural iNOS gene on chromosome 10. Analysis of the LEW and BN iNOS promoters and coding regions, together with the mapping data, suggest that cis-regulating elements are not involved in the regulation of the nitric oxide difference between LEW and BN. As possible candidates for trans-regulation of the nitric oxide difference, IFN[alpha]/[beta] and TNF[alpha] were analyzed. Results show that (1) IFN[alpha]/[beta] remains a good candidate for regulation of the nitric oxide difference between LEW and BN and (2) TNF[alpha], although necessary for nitric oxide production, does not contribute to the high nitric oxide phenotype. I have identified a novel phenotypic difference between LEW and BN rats. Specifically, naive BN rats display high numbers of eosinophils as compared to naive LEW rats. Genetic analysis using the (LEWxBN)xBN backcross, led to the identification of a strong suggestive locus on chromosome 2 associated with this phenotype. The high nitric oxide and high eosinophil phenotypes coexist and are regulated by distinct genetic factors. Both phenotypes may have direct relevance to the susceptibility of LEW and BN rats to autoimmune diseases.
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Details
- Title
- Analysis of the high nitric oxide and high eosinophil phenotypes in the brown Norway rat
- Creators
- Ana Irina Gabrea
- Contributors
- Elizabeth P. Blankenhorn (Advisor) - Drexel University, Allegheny University of the Health Sciences (1996-1998)
- Awarding Institution
- Allegheny University of the Health Sciences
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Allegheny University of the Health Sciences; Philadelphia, Pennsylvania
- Number of pages
- xviii, 164 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology [Historical]; Allegheny University of the Health Sciences (1996-1998); School of Medicine (1996-1998)
- Other Identifier
- 991021888757904721