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Evaluation of the physiological functions of bleomycin hydrolase in the murine CNS

Montoya, Susana Elizabeth (2004) Evaluation of the physiological functions of bleomycin hydrolase in the murine CNS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Montoya, Susana Elizabethsemst29@pitt.eduSEMST29
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairReynolds, Ian Jiannmda@pitt.eduIANNMDA
Committee MemberHomanics, Gregg Ehomanicsge@anes.upmc.eduGEH2
Committee MemberRomero, Guillermo Gggr@pitt.eduGGR
Committee MemberLazo, John Slazo@pitt.eduLAZO
Committee MemberFerrell, Robert Erferrell@helix.hgen.pitt.eduRFERRELL
Committee MemberPerez, Ruth Gperezrg@pitt.eduPEREZRG
Date: 4 May 2004
Date Type: Completion
Defense Date: 26 March 2004
Approval Date: 4 May 2004
Submission Date: 30 April 2004
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: bleomycin hydrolase; cysteine protease; cytokine; knockout mouse; trinucleotide repeat
Other ID:, etd-04302004-110359
Date Deposited: 10 Nov 2011 19:43
Last Modified: 19 Dec 2016 14:35


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