Regulation of Heat Shock Transcription Factor in Long-lived Animals

长寿动物热激转录因子的调节

• 批准号: 7795985
• 负责人: Ao-Lin Allen Hsu
• 金额: $ 24.68万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795985
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Age; Age of Onset; Aging; Aging-Related Process; Animal Model; Animals; Antibodies; Bacteria; Binding Proteins; Biochemical; Biochemical Genetics; Biological Assay; Biological Process; Caenorhabditis elegans; Candidate Disease Gene; Cell Nucleus; Cells; Co-Immunoprecipitations; Consensus; DNA Binding; Data; Disease; Double-Stranded RNA; EMSA; Family; Gene Mutation; Genes; Genetic; Genetic Epistasis; Genetic Screening; Goals; Heat Stress Disorders; Heat shock proteins; Heat-Shock Response; Immunoprecipitation; Insulin; Knowledge; Life; Longevity; Mass Spectrum Analysis; Mediating; Molecular; Molecular Chaperones; Mus; Mutate; Mutation; Nuclear; Organism; Output; Pathway interactions; Pattern; Peptides; Phenotype; Phosphorylation; Phosphorylation Site; Physiological; Play; Post-Translational Protein Processing; Precipitation; Process; Proteins; Proto-Oncogene Proteins c-akt; RNA Interference; Regulation; Reporting; Research; Resistance; Role; Signal Pathway; Signal Transduction; Stimulus; Stress; Survival Analysis; Testing; Transgenic Animals; Transgenic Organisms; Vertebrates; Western Blotting; age related; base; biological adaptation to stress; combat; crosslink; emerging adult; fly; gene function; genetic analysis; genome-wide; heat shock transcription factor; insight; longevity gene; mutant; novel; novel therapeutics; protein protein interaction; receptor; research study; response; tool; transcription factor

DESCRIPTION (provided by applicant): Genetic studies have clearly shown that the rate of aging, like many other biological processes, is subject to regulation. Our previous results suggested that the C. elegans heat-shock transcription factor (HSF-1), a master regulator of the cellular response to heat stress, acts in concert with the insulin/IGF-1-like signaling networks to regulate the rate of aging and the onset of age-related disease. By understanding how HSF-1 influences the aging process, the ultimate goal of our research is to develop new therapeutic strategies for combating age-related disease. We believe that HSF-1 plays a crucial role in the DAF-2 insulin/IGF-1-like signaling network to influence longevity. We have previously demonstrated that the rate of aging can be influenced by the level of HSF-1 activity in C. elegans, and that HSF-1 activity is required for daf-2 mutations to extend lifespan. Our recent findings suggest that the activity of HSF-1, like DAF-16, can be regulated directly by the DAF-2 insulin/IGF-1-like signaling. In addition, we have identified two novel genes, ddl-1 and ddl-2, that might influence longevity by negatively regulating the HSF-1 activity. Based on these observations, this proposal will focus on: 1) Determining the role of HSF-1 in the insulin/IGF-1-like signaling network to influence aging. In the proposed studies, we will determine how the DAF-2 pathway regulates the activity of HSF-1, and how HSF-1 interacts with other components of the DAF-2 pathway. 2) Characterizing two novel longevity genes, ddl-1 and ddl-2, that might function in the HSF-1 pathway to determine longevity. We will examine whether HSF-1 activity is regulated by ddl-1 and ddl-2, and whether these two genes exert their function by physically interacting with HSF-1. We will also investigate when and where ddl-1 and ddl-2 function to regulate longevity. 3) Identifying proteins that can regulate the activity of HSF-1 via protein-protein interactions. Previous studies in vertebrates suggest that the activity of HSF is often regulated by the interaction of HSF and its binding proteins. We will identify the proteins that may interact with HSF-1 by immuno-precipitation and mass spectrometry and confirm their role in determining lifespan. 4) Identifying additional genes in the HSF-1 pathway to regulate the rate of aging and stress resistance. We will perform genetic screens to identify mutations that can either suppress or enhance the phenotypes observed in hsf-1 over-expressing animals.

描述（由申请人提供）：遗传学研究清楚地表明，衰老速度与许多其他生物过程一样，受到调节。我们之前的结果表明，线虫热休克转录因子（HSF-1）是细胞对热应激反应的主要调节因子，与胰岛素/IGF-1样信号网络协同作用，调节衰老速度和与年龄相关的疾病的发生。通过了解 HSF-1 如何影响衰老过程，我们研究的最终目标是开发新的治疗策略来对抗与年龄相关的疾病。我们相信 HSF-1 在 DAF-2 胰岛素/IGF-1 样信号网络中发挥着至关重要的作用，从而影响寿命。我们之前已经证明，秀丽隐杆线虫的衰老速度可能受到HSF-1活性水平的影响，并且HSF-1活性是daf-2突变延长寿命所必需的。我们最近的研究结果表明，HSF-1 的活性与 DAF-16 一样，可以通过 DAF-2 胰岛素/IGF-1 样信号传导直接调节。此外，我们还发现了两个新基因 ddl-1 和 ddl-2，它们可能通过负向调节 HSF-1 活性来影响寿命。基于这些观察，该提案将重点关注：1）确定HSF-1在胰岛素/IGF-1样信号网络中影响衰老的作用。在拟议的研究中，我们将确定 DAF-2 途径如何调节 HSF-1 的活性，以及​​ HSF-1 如何与 DAF-2 途径的其他成分相互作用。 2) 表征两个新的长寿基因 ddl-1 和 ddl-2，它们可能在 HSF-1 途径中发挥作用，从而决定寿命。我们将检查HSF-1活性是否受ddl-1和ddl-2调节，以及这两个基因是否通过与HSF-1的物理相互作用来发挥其功能。我们还将研究 ddl-1 和 ddl-2 何时何地发挥调节寿命的作用。 3) 鉴定可通过蛋白质-蛋白质相互作用调节HSF-1活性的蛋白质。先前对脊椎动物的研究表明，HSF 的活性通常受到 HSF 与其结合蛋白的相互作用的调节。我们将通过免疫沉淀和质谱鉴定可能与 HSF-1 相互作用的蛋白质，并确认它们在决定寿命中的作用。 4) 鉴定HSF-1途径中调节衰老速度和抗应激能力的其他基因。我们将进行基因筛选，以确定可以抑制或增强 hsf-1 过度表达动物中观察到的表型的突变。