Effect of Thymidine Analogs on Neural Stem/Progenitor Cells

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DESCRIPTION (provided by applicant): Thymidine analogs are synthetic molecules that can substitute for thymidine when new DNA is copied during cell division. Some thymidine analogs kill cells and viruses because they act as DNA "chain terminators" by preventing the successful duplication of chromosomes. Other thymidine analogs do terminate growing DNA chains when they substitute for thymidine, and are useful as tools for "birthdating" cells because they can mark the precise time that a cell has undergone division. AZT is a chain-terminating thymidine analog that stops retrovirus replication by interfering with the enzyme reverse transcriptase, which is responsible for copying retroviral RNA into DNA. BrdU is a birthdating thymidine analog that has been used extensively in studies of neural stem cells. These proposed studies will examine both analogs in the context of adult neurogenesis. Specifically, preliminary studies indicate that both AZT and BrdU have unexpectedly deleterious effects on the ability of neural stem cells to continue dividing and making new neurons, both in vitro and in vivo. Furthermore, this effect -while initially subtle- progressively worsens as cells continue to replicate, suggesting that these thymidine analogs interfere with the enzyme telomerase which is responsible for adding DNA to specialized regions of chromosomes, the telomeres, during division. If AZT has a neurotoxic effect on neural stem cells, it is possible that antiretroviral therapy could contribute to, or exacerbate patients' neurological symptoms. Insights gained from these studies may lead to adjunct treatments that could prevent the interference of telomerase enzyme activity while preserving the therapeutic interference with viral reverse transcriptase. Additionally, establishing a role for BrdU in telomerase interference has wide scientific ramifications for the use of this molecule both in studies of neurogenesis - since BrdU incorporation may significantly alter the subsequent behavior of cells- and as a potential anti- cancer agent -since disruption of telomerase is a potential therapeutic strategy to slow tumor progression. Finally, if these analogs interfere with telomerase, a reverse transcriptase that copies RNA into DNA, they both may potentially interfere with other cellular reverse transcriptases that are important for epigenetic gene regulation, and may have severe consequences for normal cell function.