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Generation and Characterization of CXCR3 Bicistronic Reporter Mice and CXCR3 Transgenic Mice

Oghumu, Steve Onyeka

Abstract Details

2010, Doctor of Philosophy, Ohio State University, Microbiology.

CXCR3 belongs to a group of seven transmembrane G-protein coupled chemokine receptors which participate in the coordination of leukocyte recruitment involved in homeostasis as well as in innate and adaptive immune responses. This chemokine receptor has been shown in numerous studies to play a vital role in the regulation of immunity to viral, bacterial and parasitic infectious diseases as well as in autoimmune disorders, transplant rejection and cancer. However, the mechanisms by which CXCR3 mediates its immunoprotective or pathologic actions in various disease conditions are quite complex and still not completely understood.

The potential of tracking CXCR3 expressing cells in vivo without interfering with cellular receptor function led us to explore the development of a CXCR3 IRES bicistronic EGFP reporter (CIBER) mouse, which enables visualization of CXCR3 mRNA transcript levels in cells via fluorescence of an EGFP reporter. Analysis of T cells from CIBER mouse revealed faithful and proportionate EGFP production by CXCR3 expressing cells. Further characterization using contact hypersensitivity, bacterial and fungal infection models was performed to investigate a role for CXCR3 in these inflammatory disease processes. The utility of these mice in live in vivo cell imaging using intra vital microscopy was also demonstrated. Our results indicate that CIBER mouse will serve as a valuable tool in further understanding CXCR3 regulation, function and cellular expression which could potentially aid in the development of new immunotherapeutic strategies against infectious, neoplastic and autoimmune diseases.

As CXCR3 has been shown to be critical for immunity against a host of infectious diseases, we explored the consequences of transgenic overexpression of CXCR3 in T cells by generating a CXCR3 transgenic mouse in which CXCR3 is expressed under the control of a human CD2 promoter. In vitro analysis revealed cell surface expression of CXCR3 in virtually all T cells and active migration of transgenic mouse T cells in response to CXCR3 ligands in vivo. We further analyzed the phenotype of the CXCR3 transgenic mouse during infection with Leishmania major, Salmonella typhimurium and Histoplasma capsulatum in comparison with WT and cxcr3-/- mice to determine a potential role for CXCR3 in these infections. CXCR3 transgenic mice demonstrated increased resistance to L. major but were more susceptible to H. capsulatum and S. typhimurium than in WT and cxcr3-/- mice. We anticipate that our understanding of the role of CXCR3 in disease will be greatly enhanced by using CXCR3 transgenic mice.

These newly generated CIBER mice and CXCR3 transgenic mice have been shown to be tremendous tools that will potentially contribute to our understanding of CXCR3 regulation, expression and function. We believe that these genetically modified mouse strains will help to further define the role of CXCR3 in homeostatic processes as well as in immunity and pathology of a wide range of infectious, autoimmune and neoplastic diseases.

Abhay Satoskar (Committee Chair)
Daniel Wozniak (Committee Member)
William Lafuse (Committee Member)
Marshall Williams (Committee Member)

Recommended Citations

Citations

  • Oghumu, S. O. (2010). Generation and Characterization of CXCR3 Bicistronic Reporter Mice and CXCR3 Transgenic Mice [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1274927351

    APA Style (7th edition)

  • Oghumu, Steve. Generation and Characterization of CXCR3 Bicistronic Reporter Mice and CXCR3 Transgenic Mice. 2010. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1274927351.

    MLA Style (8th edition)

  • Oghumu, Steve. "Generation and Characterization of CXCR3 Bicistronic Reporter Mice and CXCR3 Transgenic Mice." Doctoral dissertation, Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1274927351

    Chicago Manual of Style (17th edition)