ASSOCIATION OF TELOMERASE WITH TELOMERES IN HUMAN CELLS

端粒酶与人类细胞端粒的关联

• 批准号: 8357184
• 负责人: Diego Loayza
• 金额: $ 11.92万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357184
• 关键词: Accounting; Basic Science; Binding; Biochemical; Biological Assay; Cell division; Cells; Center for Translational Science Activities; Chromosomal Stability; Chromosomes; Complex; Ensure; Enzymes; Event; Foundations; Funding; Genes; Goals; Grant; Health; Human; Laboratories; Length; Malignant Neoplasms; National Center for Research Resources; Nucleotides; Principal Investigator; Process; Regulation; Research; Research Infrastructure; Resources; Role; Site; Source; Telomerase; Telomere Maintenance; Time; Tumor Suppressor Proteins; United States National Institutes of Health; Work; cancer cell; career development; college; cost; health disparity; protein complex; senescence; telomerase reverse transcriptase; telomere

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Telomeres are essential for chromosome stability. They ensure effective protection of chromosome ends, and are replicated by a dedicated enzyme, the telomerase reverse transcriptase. Telomeres consist of long (2-10kb) repeats of the TTAGGG sequence and end with a150-300 nucleotides-long TTAGGG single stranded overhang. The six protein complex shelterin specifically binds to telomeres, regulates their length and replication, and ensures their protection. The action of telomerase is negatively regulated by shelterin, accounting for stable average telomere length over time, in cells that express the enzyme. The events involved in this regulation are unclear. The central hypothesis of this proposal is that the recruitment of telomerase is regulated by the shelterin complex. The initial objective will be to initially develop and adapt biochemical assay to quantitatively detect telomerase at chromosome ends (Aim 1). These assays will lay the foundation for the analysis of the role of shelterin in the recruitment of the enzyme to chromosome ends (Aim 2). Other non-shelterin components will be analyzed for their potential positive role in telomerase recruitment (Aim 3). The final specific aim of this proposal outlines the goals for the PI's career development, as well as the plan for the inclusion of the PI and laboratory's efforts into the RCMI Gene Center's goals at Hunter College. The understanding of how telomerase is regulated at its site of action is relevant to cancer at the cellular level. All cancer cells have ultimately activated a mechanism of telomere maintenance with provides them with infinite replicative potential. In the absence of telomere maintenance during cell division, human cells eventually cease to divide, a process called senescence, which is an important tumor suppressor mechanism. Therefore, the proposed work will have high impact on human health.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 端粒对于染色体稳定性至关重要。它们确保对染色体末端的有效保护，并通过专用酶（端粒酶逆转录酶）进行复制。端粒由 TTAGGG 序列的长 (2-10kb) 重复序列组成，并以 150-300 个核苷酸长的 TTAGGG 单链突出端结束。六种蛋白质复合物庇护蛋白与端粒特异性结合，调节端粒的长度和复制，并确保其受到保护。在表达端粒酶的细胞中，端粒酶的作用受到庇护蛋白的负向调节，从而导致随时间的推移保持稳定的平均端粒长度。该法规涉及的事件尚不清楚。 该提议的中心假设是端粒酶的募集是由庇护蛋白复合物调节的。最初的目标是初步开发和调整生化测定法以定量检测染色体末端的端粒酶（目标 1）。这些分析将为分析其作用奠定基础。 保护蛋白参与将酶招募到染色体末端的过程（目标 2）。将分析其他非庇护成分在端粒酶招募中的潜在积极作用（目标 3）。 该提案的最终具体目标概述了 PI 职业发展的目标，以及将 PI 和实验室的努力纳入亨特学院 RCMI 基因中心目标的计划。 了解端粒酶如何在其作用位点进行调节与细胞水平上的癌症相关。所有癌细胞最终都激活了端粒维持机制，为它们提供了无限的复制潜力。在细胞分裂过程中缺乏端粒维持的情况下，人类细胞最终会停止分裂，这一过程称为衰老，这是一种重要的肿瘤抑制机制。因此，拟议的工作将对人类健康产生重大影响。