Elucidating the molecular mechanisms underlying quiescence entry

阐明进入静止的分子机制

• 批准号: 9325283
• 负责人: MARLA M SPAIN
• 金额: $ 5.71万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325283
• 关键词: Age Distribution; Aging; Alpha Cell; Animal Model; Binding; Bioinformatics; Bromodeoxyuridine; Candidate Disease Gene; Cell Cycle Progression; Cell Separation; Cell Survival; Cells; ChIP-seq; Characteristics; Chromatin; Chromatin Remodeling Factor; Complex; Cues; DNA biosynthesis; DNA replication origin; Data; Defect; Development; Disease; Event; Failure; Gene Expression Profiling; Genes; Genetic Transcription; Glucose; Growth and Development function; Health; Histone Deacetylase; Histone Deacetylation; Human; Laboratories; Lead; Longevity; Malignant Neoplasms; Measures; Mediating; Methods; Molecular; Nucleosomes; Nutrient; Organism; Pathway interactions; Population; Positioning Attribute; Premature aging syndrome; Process; Regulation; Regulatory Pathway; Research; Role; Saccharomycetales; Signal Pathway; Signal Transduction; Signaling Protein; Stem cells; Therapeutic; Time; Transcriptional Regulation; Yeasts; cell growth regulation; design; exhaust; experimental study; insight; mutant; new therapeutic target; novel; programs; promoter; response; targeted treatment; transcription factor; transcriptome; transcriptomics

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. !

项目摘要/摘要 细胞是否分裂的决定是一个高度受监管且极其重要的过程 从酵母菌到人类。大多数电池保持在可逆的非分裂状态，称为 在它们一生的大部分时间里都处于静止状态。尽管一些环境信号以及信号 已经确定了响应它们以促进静止进入的途径和基因， 启动静止程序的分子机制还不是很清楚。 定义这些机制对于我们理解静默的错误调节是至关重要的 会导致发育缺陷、过早衰老和癌症等疾病。酵母细胞 进入与人类细胞类似的静止期，但这样做是为了应对营养限制。酵母菌 因此，在实验室中可以很容易地操纵静止程序。此外，信号转导通路 被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，在其中 研究静息调节机制。以前关于静止进入的研究依赖于 由于难以识别，通过比较静止细胞和分裂细胞获得的信息 进入之前处于静止状态的细胞。因为静止程序早在细胞开始之前就开始了 实际上，我建议开发一种方法来识别注定要成为 在项目开始前处于静止状态。通过分析这些细胞中的基因表达 与不会进入静止状态的细胞相比，我将阐明参与 启动静默程序。除了转录，DNA的微调调节 对环境线索作出反应的复制对所有有机体的生存都是至关重要的。通过 分析SWI/SNF染色质重塑复合体在调控复制中的作用 静止期，我将确定转录和复制是如何共同调节的，以诱导 宁静。总体而言，拟议的研究预计将定义 进入静止状态的早期阶段，并为疾病提供新的治疗靶点，例如 癌症。 好了！