The overall hypothesis of this thesis project was that bleomycin hydrolase (BLMH) has biologically specific and unique functions in the central nervous system (CNS). BLMH is a multifaceted papain superfamily cysteine protease that has importance in drug metabolism. The physiological functions of this protease are unknown as are factors regulating its expression. Immunohistochemical examination of B6.129Blmhtm1Geh/J null and control animals showed no gross abnormalities; however, marked global astrogliosis was observed in the null aged animals. To define the role of BLMH in the brain, the behavioral phenotype of hybrid [129S6-Blmhtm1Geh/J X B6.129 Blmhtm1Geh/J]F1 null and littermate controls was characterized using multiple behavioral paradigms. Deletion of Blmh was found to result in deficits among young animals in water maze probe trials. Retention of target platform location during the probe trials requires both learning and memory as well as sensory and locomoter skills. No overt sensory or motor deficits were noted in Blmh null F1 hybrids. The profile of BLMH expression and its regulation in the CNS was studied next. Inducible transcription of BLMH was evaluated in the context of a putative role in the processing of MHC I epitopes. BLMH was found to be differentially regulated in microglia and astrocytes. In microglia, Blmh protein was significantly induced by gamma interferon or tumor necrosis factor a, whereas in astrocytes, no change in protein expression was observed. Treatment of microglial derived cell lines with both gamma interferon and tumor necrosis factor a revealed synergistic effects between the cytokines. BLMH protein induction was accompanied by increased Blmh mRNA. These results suggest that cell specific regulation of BLMH is an important control mechanism for this protease. These data also provide further evidence for a targeted immune related biological function for BLMH. It is concluded that BLMH potentially has multiple unique and biologically important functions within the brain.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04302004-110359 |
| Date | 04 May 2004 |
| Creators | Montoya, Susana Elizabeth |
| Contributors | Robert E. Ferrell, Gregg E. Homanics, Ruth G. Perez, Ian J. Reynolds, Guillermo G. Romero, John S. Lazo |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04302004-110359/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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