Investigate the Transcriptional Co-factors of DAF-16/FOXO in C. elegans

研究线虫中 DAF-16/FOXO 的转录辅因子

• 批准号: 8513205
• 负责人: Siu Sylvia Lee
• 金额: $ 28.53万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513205
• 关键词: Affect; Aging; Biochemical; Biological Process; Biology of Aging; Caenorhabditis elegans; Cell Nucleus; Cells; Chromatin; Development; Diabetes Mellitus; Disease; Dissection; Environment; Family; Funding; Future; Gene Expression Regulation; Gene Targeting; Genetic; Genetic Models; Genetic Transcription; Goals; Homologous Gene; Human; Insulin; Insulin-Like Growth Factor I; Integration Host Factors; Investigation; Laboratories; Longevity; Malignant Neoplasms; Mammals; Mediating; Metabolism; Modeling; Molecular; Molecular Profiling; Nature; Nuclear; Nuclear Protein; Organism; Orthologous Gene; Output; Pathogenesis; Pathology; Play; Proteins; Regulation; Reporting; Resources; Role; Series; Signal Transduction; Specificity; Stimulus; System; Testing; age related; biological adaptation to stress; human disease; insight; novel; promoter; protein complex; research study; therapeutic development; transcription factor

Project Summary: Transcription factors of the DAF-16/FOXO family are evolutionarily conserved master regulators capable of integrating diverse environmental stimuli and coordinating development, metabolism, stress responses, and longevity. Deregulation of FOXO proteins in humans is well known to play a key role in age- related diseases such as cancer and diabetes. For DAF-16/FOXOs to achieve their multi-faceted and central roles, their transcriptional activities need to be exquisitely regulated; however, the mechanisms underlying the regulation of DAF-16/FOXO-mediated gene transcription are largely unknown. The long-term goal of this proposal is to elucidate comprehensively how DAF-16/FOXO transcriptional activities are regulated in the nucleus and how this regulation contributes to longevity determination. We recently discovered that the C. elegans ortholog of the nuclear protein host cell factor 1 (HCF-1) modulates longevity by functioning as a DAF-16 co-factor that inhibits DAF-16-mediated gene regulation. Since HCF-1 is the first DAF-16 negative co-factor reported in C. elegans, this finding provides an important entry point for further investigation of how DAF-16 transcriptional activities are regulated. In Aim 1, we propose to test the hypothesis that the specificity of DAF-16-mediated transcriptional output is determined by the interplay between HCF-1 and other DAF-16 co-factors. In Aim 2, we propose to test the hypothesis that HCF-1 forms a regulatory network with SIR-2.1 to regulate DAF-16 transcriptional activity on specific target genes. In Aim 3, we propose to identify additional transcription and chromatin factors that regulate DAF-16-mediated gene transcription. Since DAF-16 and its co-factors (HCF-1, SIR-2.1, SMK-1, BAR-1, CTBP-1) are all highly conserved, findings from our studies will provide important insights into FOXO regulation and longevity determination in mammals. Moreover, the mammalian orthologs of DAF-16 and its co-factors are known to play key roles in the pathogenesis of a number of human diseases, such as cancer and diabetes, findings from our studies may inspire future therapeutic development aiming to alleviate some of these age-related pathologies in humans.

项目总结： DAF-16/FOXO家族转录因子是进化上保守的主调控因子 能够整合各种环境刺激，协调发展、新陈代谢、压力 反应，和长寿。众所周知，FOXO蛋白在人类衰老过程中起着关键作用。 癌症和糖尿病等相关疾病。为DAF-16/FOXO实现其多面性和 核心作用，它们的转录活动需要被精细地调控；然而，机制 DAF-16/FOXO介导的基因转录的调控机制在很大程度上尚不清楚。长期的 这项建议的目的是全面阐明DAF-16/FOXO转录活性是如何 以及这种调控是如何决定长寿的。我们最近 发现线虫核蛋白宿主细胞因子1(HCF-1)的同源基因调节寿命 通过发挥DAF-16辅助因子的作用，抑制DAF-16介导的基因调控。由于HCF-1是第一个 在线虫中报告的DAF-16负辅助因子，这一发现为进一步研究提供了一个重要的切入点 研究DAF-16转录活性是如何被调控的。在目标1中，我们建议测试 DAF-16介导的转录输出的特异性由相互作用决定的假说 HCF-1和其他DAF-16辅助因子之间的关系。在目标2中，我们建议检验hcf-1形成的假设。 含有SIR-2.1的调控网络，用于调控DAF-16在特定靶基因上的转录活性。在AIM 3，我们建议确定额外的转录和染色质因子来调节DAF-16介导的基因 抄写。由于DAF-16及其辅助因子(HCF-1、SIR-2.1、SMK-1、BAR-1、CTBP-1)均高度 保守地说，我们的研究结果将为FOXO的监管和寿命提供重要的见解 哺乳动物的决心。此外，已知DAF-16及其辅助因子在哺乳动物中的同源基因 在许多人类疾病的发病机制中发挥关键作用，如癌症和糖尿病 我们的研究可能会启发未来的治疗发展，旨在缓解一些与年龄有关的问题 人类的病理学。