Gene Expression in Aging and Development

衰老和发育中的基因表达

• 批准号: 7524612
• 负责人: Woodring Erik Wright
• 金额: $ 39.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-01-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7524612
• 关键词: Address; Aging; Biological; Biological Assay; Biology; Cell Aging; Cell Cycle; Cell physiology; Cells; Chromosomes; DNA; DNA Damage; Development; Diploid Cells; Disease; Elongation by Telomerase; Enzymes; Event; Gene Expression; Genetic Recombination; Human; Investigation; Knowledge; Length; Malignant Neoplasms; Molecular; Numbers; Pharmaceutical Preparations; Process; Public Health; Regulation; Repetitive Sequence; Signal Transduction; Site; Standards of Weights and Measures; Structure; Surrogate Markers; System; Techniques; Telomerase; Telomere Capping; Telomere Maintenance; Telomere Pathway; Telomere Recombination; Telomere Shortening; Telomere-Binding Proteins; Time; age related; base; cancer cell; novel therapeutics; prevent; repaired; restriction enzyme; telomere; therapeutic target; tumor; Address; Aging; Biological; Biological Assay; Biology; Cell Aging; Cell Cycle; Cell physiology; Cells; Chromosomes; DNA; DNA Damage; Development; Diploid Cells; Disease; Elongation by Telomerase; Enzymes; Event; Gene Expression; Genetic Recombination; Human; Investigation; Knowledge; Length; Malignant Neoplasms; Molecular; Numbers; Pharmaceutical Preparations; Process; Public Health; Regulation; Repetitive Sequence; Signal Transduction; Site; Standards of Weights and Measures; Structure; Surrogate Markers; System; Techniques; Telomerase; Telomere Capping; Telomere Maintenance; Telomere Pathway; Telomere Recombination; Telomere Shortening; Telomere-Binding Proteins; Time; age related; base; cancer cell; novel therapeutics; prevent; repaired; restriction enzyme; telomere; therapeutic target; tumor

DESCRIPTION (provided by applicant): Human telomeres (the structures that cap the ends of chromosomes) are composed of many kilobases of the repetitive sequence TTAGGG that together with telomere binding proteins prevent the cell from recognizing the ends as DNA breaks needing repair. Telomeres shorten due to incomplete DNA lagging strand synthesis/processing, and cellular senescence occurs when some have shortened sufficiently to induce a DNA damage signal. Cancer cells escape the proliferative limits of replicative aging by one of two mechanisms. Most frequently they up-regulate the expression of telomerase, an enzyme capable of adding telomere repeats to the ends of the chromosomes and maintaining their length. Much less frequently tumors activate a recombination-based ALT (Alternative Lengthening of Telomeres) mechanism for maintaining the ends of their chromosomes. The detailed structure of telomeres is very difficult to study because of the lack of restriction enzyme sites in the repetitive TTAGGG sequence (which prevents standard molecular biological approaches) and the fact that each diploid cell contains 92 telomeres (23 chromosomes x 2 ends x two copies of each). We have developed techniques that now permit us to address a large number of fundamental issues in telomere biology. In Specific Aim 1, we will determine how rapidly following replication the mature structure of the 3' overhangs are established, what factors influence the timing or extent of this processing, when telomerase acts to elongate the G-strand, how much telomerase can add, how telomerase action and the C-strand fill-in are coordinated, and how special structures called t- loops are unfolded and reformed during replication. Aim 2 explores the relationships between the mechanism that prevents restriction enzymes from digesting the region adjacent to the telomere and that which normally blocks recombination from occurring within the highly repetitive telomeric sequences. Investigations will include how these mechanisms are changed in cells using the ALT mechanism, and if many different types of ALT pathways exist. The results of these studies will not only advance our understanding of basic telomere regulation, but will also identify new therapeutic targets for inhibiting telomere maintenance in cancer (steps in telomerase elongation or ALT recombination) or slowing telomere shortening in age-related diseases. PUBLIC HEALTH RELEVANCE: Telomeres cap the ends of all of our chromosomes and protect them from degradation. Telomere shortening causes replicative aging, and cancer cells are immortal because they acquire mechanisms to prevent this. Knowledge of the structure and processing of telomeres and the mechanisms by which they are maintained will provide targets for the development of new drugs to treat cancer and age-related diseases.

描述（由申请人提供）：人类端粒（限制染色体末端的结构）由重复序列TTAGGG的许多千射线组成，它们与端粒结合蛋白一起阻止细胞识别出末端，因为DNA断裂需要修复。由于不完全的DNA滞后链合成/加工而导致的端粒缩短，并且当一些人足够缩短以诱导DNA损伤信号时，会发生细胞衰老。癌细胞通过两种机制之一逃脱了复制衰老的增殖极限。最常见的是，它们上调端粒酶的表达，端粒酶是一种能够在染色体末端添加端粒重复并保持其长度的酶。肿瘤的频率要少得多，可以激活基于重组的ALT（端粒的替代延长）机制来维持其染色体的末端。端粒的详细结构很难研究，因为重复的TTAGGG序列中缺乏限制性酶位点（可以防止标准分子生物学方法），并且每个二倍体细胞都包含92个端粒（23个染色体x 2 X 2 2 eent x X 2 eent x二副本）。我们已经开发了现在可以解决端粒生物学中大量基本问题的技术。在特定的目标1中，我们将确定复制后3'突出的成熟结构的迅速，什么因素会影响该处理的时间或程度，而当端粒酶起作用以拉长G链，可以添加多少端粒酶，端粒酶的作用和C-strand填充的方式以及c-strand填充的方式，并在t-the t-loops中进行了调整。 AIM 2探讨了阻止限制酶消化与端粒相邻的区域的机制之间的关系，通常会阻止重组在高度重复的端粒序列中发生的重组。研究将包括使用ALT机制在细胞中如何改变这些机制，以及是否存在许多不同类型的ALT途径。这些研究的结果不仅将提高我们对基本端粒调节的理解，还将确定抑制癌症中端粒维持的新治疗靶标（端粒延伸或ALT重组的步骤）或减慢与年龄相关疾病的端粒缩短。公共卫生相关性：端粒限制我们所有染色体的末端，并保护它们免受降解。端粒缩短会导致复制衰老，癌细胞是不朽的，因为它们获得了防止这种情况的机制。了解端粒的结构和加工及其维持的机制，将为开发新药物治疗癌症和与年龄相关的疾病提供目标。