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OXIDATIVE MODIFICATION OF INTRA AND EXTRACELLULAR PROTEASES IN THE PATHOLOGY OF GLAUCOMA

Govindarajan, Bharathi
http://rave.ohiolink.edu/etdc/view?acc_num=case1222729349

Abstract Details

2008, Doctor of Philosophy, Case Western Reserve University, Chemistry.
Primary open angle glaucoma (POAG) is a disease that affects more than 70 million people worldwide. The pathology of glaucoma includes an increase in the intraocular pressure, followed by irreversible damage to the optic nerve leading to progressive blindness. We investigated protein modifications by two lipid derived oxidation products namely iso[4]levuglandin E2(isoLGE2) and 4-hydroxy-nonenal (HNE), in the human trabecular meshwork (TM) and optic nerve, and their impact on specific proteins in POAG. Calpain-1 inhibitors have been proposed as potential neuroprotective agents in glaucoma and other neurodegenerative diseases. Our studies have indicate that calpain-1 is potentially modified by iso[4]LGE2 in the glaucomatous TM. Iso[4]LGE2-modified calpain-1 forms aggregates, which cannot be degraded by the proteasomal machinery of the cell. Calpain-1 protein expression is upregulated in the glaucomatous optic nerve (ON) without modification by iso[4]LGE2. Differences detected in the processing of calpain-1 in the anterior versus posterior segment of the eye indicate that it is vital to look into the levels of proteins in the entire organ before embarking on neuroprotection strategies. Extracellular and intracellular proteases have been implicated in the pathology of glaucoma. We found that the levels of active matrix metalloproteinase MMP-2 are elevated in the glaucomatous TM. This is an important discovery that is consistent with another observation, that the levels of fibronectin, a substrate of MMP-2, are decreased in the glaucomatous TM. Immunoprecipitation analysis indicated that both MMP-2 and fibronectin are modified by HNE, in the normal and glaucomatous TM. Destruction of the optic nerve head (ONH) and activation of astrocytes has been reported in the glaucomatous ONH as a consequence of increased intraocular pressure. We found that pressure treated astrocytes show an increase in levels of iso[4]LGE2-protein adducts. Post pressure treatment with the trapping agent pyridoxamine is an effective means of capturing iso[4]LGE2-modified proteins. Lipid modifications of proteases and their substrates contribute to the pathophysiology of glaucoma and may be potential therapeutic targets for the treatment and prevention of late stage complications of this disease.
Robert Salomon, PhD (Advisor)
Vernon Anderson, PhD (Committee Chair)
John Protasiewicz, PhD (Committee Member)
John Stuehr, PhD (Committee Member)
Joe Hollyfield, PhD (Other)
Bela Anand-Apte, M.B.B.S, Phd (Advisor)
318 p.
Biochemistry; Chemistry; Ophthalmology
Glaucoma; oxidative stress; lipid peroxidation; oxidative modification; proteases

Recommended Citations

Citations

  • Govindarajan, B. (2008). OXIDATIVE MODIFICATION OF INTRA AND EXTRACELLULAR PROTEASES IN THE PATHOLOGY OF GLAUCOMA [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1222729349

    APA Style (7th edition)

  • Govindarajan, Bharathi. OXIDATIVE MODIFICATION OF INTRA AND EXTRACELLULAR PROTEASES IN THE PATHOLOGY OF GLAUCOMA. 2008. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1222729349.

    MLA Style (8th edition)

  • Govindarajan, Bharathi. "OXIDATIVE MODIFICATION OF INTRA AND EXTRACELLULAR PROTEASES IN THE PATHOLOGY OF GLAUCOMA." Doctoral dissertation, Case Western Reserve University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1222729349

    Chicago Manual of Style (17th edition)

case1222729349
570
© 2008, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.