Dissertation
Genetic mapping and analysis of disease susceptibility in a mouse model of multiple sclerosis
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2017
DOI:
https://doi.org/10.17918/etd-7523
Abstract
Multiple sclerosis (MS) is a debilitating chronic inflammatory disease of the nervous system that affects approximately 2.3 million individuals worldwide, and is influenced by environmental and genetic factors. The disease course in both MS and experiential allergic encephalomyelitis (EAE), the most commonly used animal model for MS, depends on a central nervous system (CNS)-directed autoimmune inflammatory response. While over 200 MS susceptibility loci have been identified in genome wide association studies (GWAS), the underlying mechanisms whereby they contribute to disease susceptibility remain ill-defined. Conventional laboratory mouse strains are useful in identifying genes that control disease-relevant phenotypes, but they are hindered by their limited genetic diversity. Consomic strains, such as the B6 x PWD panel, can overcome this issue through introgression of naturally derived (wild) allelic variants onto a uniform genetic background. Work with this panel indicates susceptibility to EAE is highly influenced by genome-wide genetic diversity that is a natural consequence of the profound genetic control exerted upon the immune transcriptome. We have chosen to study further the C57BL/6J-Chr10.3PWD/Ph/ForeJ (10.3-PWD) strain of this panel. These 10.3-PWD mice are highly resistant to EAE due to naturally derived alleles present on the distal portion of chromosome 10. QTL mapping preparatory to positional cloning indicates that the locus controlling EAE resistance resides within 73.5-95.4 Mb on chromosome 10. Several interesting candidate genes reside within this interval including Timp3 and Igf1 that are differentially expressed during the initial phases of disease within peripheral immune tissue. The peripheral immune response in this EAE resistant strain is characterized by an increase in TNF[alpha] production and a deficit in TH17 cytokine production that is not antigen-specific. Despite the TH17 difference, similar proportions of T cells are present in the CNS during the peak of disease; however, lower proportions of myeloid cells reside in the CNS of these resistant mice at this time. The differential expression (DE) of candidates Timp3 and Igf1 extends to bone marrow-derived macrophages and dendritic cells (BMDC), which may be responsible for the EAE resistant phenotype.
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Details
- Title
- Genetic mapping and analysis of disease susceptibility in a mouse model of multiple sclerosis
- Creators
- Frank M. Bearoff - DU
- Contributors
- Elizabeth P. Blankenhorn (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xv, 231 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 7523; 991014632257904721