Effect of Thymidine Analogs on Neural Stem/Progenitor Cells

描述（由申请人提供）：胸苷类似物是在细胞分裂过程中复制新DNA时可以替代胸苷的合成分子。一些胸腺嘧啶类似物杀死细胞和病毒，因为它们通过阻止染色体的成功复制而充当DNA“链终止者”。其他胸腺嘧啶类似物在替代胸腺嘧啶时确实会终止生长的DNA链，并且作为“出生日期”细胞的工具很有用，因为它们可以标记细胞经历分裂的精确时间。AZT是一种终止链的胸苷类似物，通过干扰逆转录酶来阻止逆转录病毒的复制，逆转录酶负责将逆转录病毒RNA复制到DNA中。BrdU是一种胸腺嘧啶类似物，已广泛用于神经干细胞的研究。这些拟议的研究将在成人神经发生的背景下检查这两种类似物。具体来说，初步研究表明，AZT和BrdU在体外和体内对神经干细胞继续分裂和产生新神经元的能力都有意想不到的有害影响。此外，这种效应虽然最初很微妙，但随着细胞继续复制，它会逐渐恶化，这表明这些胸腺嘧啶类似物会干扰端粒酶，而端粒酶在分裂过程中负责将DNA添加到染色体的特定区域，即端粒。如果AZT对神经干细胞有神经毒性作用，抗逆转录病毒治疗可能会导致或加重患者的神经系统症状。从这些研究中获得的见解可能会导致辅助治疗，可以防止端粒酶活性的干扰，同时保留对病毒逆转录酶的治疗干扰。此外，确定BrdU在端粒酶干扰中的作用对于该分子在神经发生研究中的应用具有广泛的科学影响——因为BrdU的掺入可能显著改变细胞的后续行为——以及作为一种潜在的抗癌剂——因为端粒酶的破坏是一种减缓肿瘤进展的潜在治疗策略。最后，如果这些类似物干扰端粒酶（一种将RNA复制成DNA的逆转录酶），它们都可能潜在地干扰其他对表观遗传基因调控重要的细胞逆转录酶，并可能对正常细胞功能产生严重后果。

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.