In this study, the adaptation and response of Aspergillus nidulans and Aspergillus
fumigatus wild type and cpcA strains to antifungal compounds were studied using cultural,
genetic and proteomic methods. CpcA is the fungal cross pathway control protein which may
also have a role in the development of resistance to antifungal that has become a major problem
in human and plant fungal diseases and many studies are devoted to address the drug resistance
mechanisms. Cell adapts itself to stress when it is subjected to a stress repeatedly. The ancestor
of CpcA, ATF4 (CREB2) has recently been found to be important in the survival of tumor cells
after starvation and nutrient limitation and these findings are expected to open new insights into
the future antifungal therapy. Fungal cross pathway control system conserves similar mechanism
with the stress response pathway in humans as a response to amino acid starvation. Fungal
adaptation to antifungal agents was studied using the genetic model A. nidulans with the
experimentally induced adaptation setup. It was concluded that A. nidulans cells are able to
adapt to antifungal. In order to understand how cell becomes resistant to a previously susceptible
agent, it is important to investigate the process when the cell encounters the agent for the first
time. Fungal cellular response to antifungal drugs was studied using the human opportunistic
pathogen A. fumigatus at the protein level. This is the first proteomic study directed to
investigate the A. fumigatus response to voriconazole (VRC). The recently developed two
dimensional gel electrophoresis approach, Fluorescence 2-D Differential Gel Electrophoresis
(DIGE) method was applied to visualize differentially expressed proteins. It was concluded that,
about 150 proteins were differentially regulated as a response to stress exerted by azole group
antifungal drugs. cpcA strains of A. nidulans and A. fumigatus were compared to wild type
strains in terms of susceptibility to various stresses, adaptation potential also at the proteome
level. The results obtained in this study showed that CpcA was important in the response of
Aspergillus to oxidative, heat stress and in the adaptation of cells to VRC and that its absence
drastically changed the cellular response to VRC at the protein level by changing the expression
of about 80 proteins. Thus, this protein is a good candidate in future as a potential drug resistance
mediator and further characterization is needed to elucidate its mechanism of action on drug
resistance.
| Identifer | oai:union.ndltd.org:METU/oai:etd.lib.metu.edu.tr:http://etd.lib.metu.edu.tr/upload/12612308/index.pdf |
| Date | 01 August 2010 |
| Creators | Amarsaikhan, Nansalmaa |
| Contributors | Ogel, Zumrut Begum |
| Publisher | METU |
| Source Sets | Middle East Technical Univ. |
| Language | English |
| Detected Language | English |
| Type | Ph.D. Thesis |
| Format | text/pdf |
| Rights | To liberate the content for METU campus |
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