Elucidating the molecular mechanisms underlying quiescence entry

项目总结/摘要 细胞是否分裂的决定是一个高度调节的，在所有生物学中都是至关重要的过程。 从酵母菌到人类。大多数细胞保持在可逆的非分裂状态， 他们一生中的大部分时间都处于平静状态。虽然一些环境信号和信号 已经确定了对它们作出反应以促进进入静止期的途径和基因， 参与启动静止程序的分子机制还没有很好地理解。 定义这些机制对于我们理解静止期的错误调节 导致发育缺陷、过早衰老和癌症等疾病。酵母细胞 进入类似于人类细胞的静止期，但这样做是对营养限制的反应。酵母 因此，在实验室中容易操作静止程序。此外，信号通路 酵母利用的蛋白质在人类中是保守的，使酵母成为一种极好的模式生物， 研究静止调节的机制。先前关于进入静止期的研究依赖于 由于难以识别，通过比较静止细胞和分裂细胞获得的信息 进入前的静止细胞。因为静止期程序早在细胞 实际上，我建议开发一种方法来识别注定要成为 在程序启动之前静止。通过分析这些细胞中的基因表达， 与不进入静止期的细胞相比，我将阐明参与细胞凋亡的分子机制。 启动静止程序除了转录，DNA的精细调节 对环境线索作出反应的复制对所有生物的生存都是必不可少的。通过 分析SWI/SNF染色质重塑复合物在调节复制过程中的作用， 进入静止期后，我将确定转录和复制是如何共同调节的， 安静总的来说，拟议的研究预计将确定潜在的机制， 进入静止期的早期阶段，并为疾病提供新的治疗靶标， 癌 !

Project Summary/Abstract The decision by a cell to divide or not is a highly regulated and vitally important process in all organisms from yeast to human. Most cells remain in a reversible non-dividing state referred to as quiescence for much of their lifetime. Although some environmental signals as well as the signaling pathways and genes that respond to them to promote quiescence entry have been identified, the molecular mechanisms involved in initiating the quiescence program are not well understood. Defining these mechanisms is essential to our understanding of how the misregulation of quiescence contributes to developmental defects, premature aging, and diseases such as cancer. Yeast cells enter quiescence similar to human cells, but do so in response to nutrient limitation. The yeast quiescence program is thus easily manipulated in the laboratory. Furthermore, the signaling pathways utilized by yeast are conserved in humans, rendering yeast an excellent model organism in which to study the mechanisms of quiescence regulation. Prior studies of quiescence entry relied on information obtained from comparing quiescent cells to dividing cells, due to difficulty in identifying quiescent cells prior to their entry. Because the quiescence program is initiated long before cells actually enter, I propose to develop a method for identifying cells that are destined to become quiescent prior to the initiation of the program. By analyzing gene expression in these cells as compared to cells that will not enter quiescence, I will elucidate the molecular mechanisms involved in initiating the quiescence program. In addition to transcription, the fine tuned regulation of DNA replication in response to environmental cues is essential to the survival of all organisms. By analyzing the role of the SWI/SNF chromatin remodeling complex in regulating replication during quiescence entry, I will determine how transcription and replication are co-regulated to induce quiescence. Overall, the proposed research is expected to define the mechanisms underlying the early stages of quiescence entry, and to provide novel therapeutic targets for diseases such as cancer. !