Functional Analysis of Cellular Quescence

细胞静止的功能分析

• 批准号: 9901407
• 负责人: MARY ANN OSLEY
• 金额: $ 31.06万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9901407
• 关键词: Adult; Affect; Animal Model; Apoptosis; Bar Codes; Biochemical; Bromodeoxyuridine; Cancer Relapse; Cell Aging; Cell Cycle; Cell model; Cells; Chronology; Comb animal structure; Complex; DNA; DNA Damage; DNA Repair; DNA biosynthesis; DNA lesion; DNA replication fork; DNA-Directed DNA Polymerase; Data; Development; Epigenetic Process; Excision; Frequencies; G0 Phase; Genetic; Genome; Genomic approach; Genomics; Growth; Health; Histones; Human; Injury; Lead; Libraries; Link; Location; Longevity; Lysine; Maintenance; Malignant Neoplasms; Maps; Measures; Methylation; Molecular; Molecular Genetics; Monitor; Mutagenesis; Mutation; Necrosis; Pathway interactions; Pattern; Peptide Initiation Factors; Phase; Phenotype; Play; Population Growth; Post-Translational Protein Processing; Proliferating; Pyrimidine Dimers; Regulation; Replication Initiation; Replication Origin; Role; S Phase; Saccharomyces cerevisiae; Saccharomycetales; Signal Transduction; Site; Stress; Supporting Cell; System; Testing; Therapeutic; Time; Tissues; UV Radiation Exposure; Ultraviolet Rays; Vertebrates; Yeasts; adult stem cell; cancer stem cell; cell regeneration; cell type; cellular longevity; chromatin modification; genetic approach; genome integrity; genome-wide; helicase; histone modification; human adult stem cell; mutant; novel therapeutics; preservation; programs; repaired; replication stress; reproductive; response; response to injury; self renewing cell; self-renewal; stem cells; targeted treatment; tissue regeneration; tumor; ultraviolet lesions

Project Summary Cellular quiescence plays a key role in adult stem cells by providing a pool of self-renewing cells that can differentiate into specific lineages to replenish cells lost from natural turnover or injury. Quiescence also protects cancer stem cells from many common therapies that target rapidly dividing tumors, and is postulated to be a major contributor to cancer relapse. Thus, understanding the regulatory mechanisms that contribute to the self-renewal, survival, and formation of quiescent cells has important implications for many aspects of human health, including tissue regeneration and cancer therapeutics. In this proposal, we will define these mechanisms using the model organism, Saccharomyces cerevisiae, where stationary phase has emerged as an excellent system to study cellular quiescence. Quiescent yeast cells represent a sub-population of growth arrested, non-dividing or G0 cells that can be isolated from a stationary phase culture in sufficient quantities for genetic, molecular, and genomic analyses. Like quiescent adult stem cells in vertebrates, quiescent yeast cells show extended viability and can re-enter the cell cycle when growth-promoting signals are restored. Moreover, the formation of these cells plays a key role in the regulation of chronological lifespan and cellular longevity. In three specific aims, we will use a combination of molecular, genetic, and genomic approaches to define the reproductive capacity of quiescent cells by following the temporal and spatial program of DNA replication upon re-entry of quiescent cells into the cell cycle (Aim1); the mechanisms involved in the repair of exogenous DNA to preserve genome integrity (Aim 2); and the histone post-translational modifications that play a role in the formation and survival of quiescent cells and thereby regulate chronological lifespan (Aim 3). The proposed studies could provide important paradigms for understanding the mechanisms that contribute to the formation and maintenance of quiescent cells in more complex developmental systems, and the relationship of quiescence to cell longevity.

项目摘要 细胞静止在成体干细胞中起着关键作用，它提供了一个自我更新的细胞库， 分化成特定的谱系，以补充因自然更新或损伤而丢失的细胞。寂静也 保护癌症干细胞免受许多针对快速分裂肿瘤的常见疗法的影响， 是癌症复发的主要原因因此，了解有助于 静止细胞的自我更新、存活和形成对许多方面都有重要意义， 人类健康，包括组织再生和癌症治疗。在本提案中，我们将定义这些 使用模式生物酿酒酵母的机制，其中固定相已经出现， 一个研究细胞静止的绝佳系统静止的酵母细胞代表生长的亚群 停滞的、非分裂的或G 0细胞，其可以从稳定期培养物中分离出足够量用于 遗传、分子和基因组分析。像脊椎动物中静止的成体干细胞一样，静止的酵母细胞 显示出延长的活力，并且当生长促进信号恢复时可以重新进入细胞周期。此外，委员会认为， 这些细胞的形成在时间寿命和细胞寿命的调节中起关键作用。在 三个具体目标，我们将使用分子，遗传和基因组方法的组合来定义 通过遵循DNA复制的时间和空间程序， 静止细胞重新进入细胞周期（Aim 1）;外源DNA修复机制 保护基因组完整性（目标2）;以及在基因组完整性中发挥作用的组蛋白翻译后修饰。 静止细胞的形成和存活，从而调节时间寿命（Aim 3）。拟议 研究可以为理解有助于形成的机制提供重要的范例 在更复杂的发育系统中，静止细胞的维持，以及 静止到细胞寿命。