Most cells throughout their existence are constantly subjected to enormous amounts of endogenous and exogenous DNA damage. The cellular response to genotoxic stressors ultimately either leads to adaptive processes that mediate cellular repair and allow for continuous cellular function or leads to cell malfunction and death. In some theories of aging this cellular malfunction is due to accumulation of unrepaired DNA damage which over time leads to progressive deterioration of tissue/organ homoeostasis and function resulting in organismal aging. The overall goal of my studies is to understand the responses to DNA damage in corneal endothelial (CE) cells whose pump and barrier functions are essential for corneal transparency and which in vivo display age-related degeneration and accumulation of DNA damage. In three complementary and related studies I have focused on how the CE is affected by genotoxic stress. In the first study I have examined the clinical application of the DNA crosslinking agent mitomycin C during photorefractive keratectomy and documented its effects on the CE such as significant accumulation of DNA lesions and elevated levels of apoptosis. In the second study I have examined the long term consequences resulting from failure to repair endogenous DNA damage in vivo. Using a DNA repair-deficient mouse strain I have observed significant premature age-related dystrophic changes in the CE that only occur in very old mice. This suggests that the CE is sensitive and vulnerable to the effects of accumulating endogenous genotoxic stress and that DNA damage may drive CE aging. In the third study I have examined how CE cell-cell communication mediated by gap junctions is affected by acute genotoxic stress. Given that gap junction intercellular communication is essential for homeostasis and associated with cell proliferation, death and survival, alterations in the gap junction protein connexin-43 may be crucial for CE cell function and viability during genotoxic stress. The key findings of all my studies elucidate the role of genotoxic stress in CE aging and identify novel responses to stresses from DNA damage. Through a greater understanding of the responses to these stressors, efforts to preserve and improve CE viability and function can be achieved.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-07252011-162750 |
| Date | 02 August 2011 |
| Creators | Roh, Daniel Sam |
| Contributors | Laura Niedernhofer, Jame Funderburgh, Charleen Chu, Sandra Murray, Carolyn Coyne |
| 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-07252011-162750/ |
| Rights | restricted, 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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