Regulation of Heat Shock Transcription Factor in Long-lived Animals

长寿动物热激转录因子的调节

基本信息

批准号：
8230617
负责人：
Ao-Lin Allen Hsu
金额：
$ 23.72万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
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/8230617
关键词：
1-Phosphatidylinositol 3-Kinase Address 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 Insulin-Like Growth Factor I 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

项目摘要

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，与许多其他生物过程一样，衰老速率受到调节。我们先前的结果表明，秀丽隐杆线虫的热震转录因子（HSF-1）是细胞对热应力反应的主要调节剂，与胰岛素/IGF-1样信号网络一致，以调节速率衰老和与年龄有关的疾病的发作。通过了解HSF-1如何影响衰老过程，我们研究的最终目标是制定与年龄相关疾病打击的新治疗策略。我们认为，HSF-1在DAF-2胰岛素/IGF-1样信号网络中起着至关重要的作用，以影响寿命。我们以前已经证明，衰老的速率可能受秀丽隐杆线虫中HSF-1活性水平的影响，并且DAF-2突变延长寿命需要HSF-1活性。我们最近的发现表明，HSF-1（例如DAF-16）的活性可以通过DAF-2胰岛素/IGF-1样信号直接调节。此外，我们已经确定了两个新型基因DDL-1和DDL-2，它们可能通过负调节HSF-1活性来影响寿命。基于这些观察结果，该建议将重点放在：1）确定HSF-1在胰岛素/IGF-1样信号网络中的作用，以影响衰老。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途径的其他组件相互作用。 2）表征两个新型寿命基因DDL-1和DDL-2，它们可能在HSF-1途径中起作用以确定寿命。我们将检查HSF-1活性是否由DDL-1和DDL-2调节，以及这两个基因是否通过与HSF-1进行物理相互作用来发挥其功能。我们还将研究何时何地DDL-1和DDL-2功能调节寿命。 3）鉴定可以通过蛋白质 - 蛋白质相互作用来调节HSF-1活性的蛋白质。先前在脊椎动物的研究表明，HSF的活性通常受HSF及其结合蛋白的相互作用调节。我们将通过免疫沉淀和质谱法确定可能与HSF-1相互作用的蛋白质，并确认其在确定寿命中的作用。 4）鉴定HSF-1途径中的其他基因以调节衰老和应激性抗性速率。我们将执行遗传筛选，以鉴定可以抑制或增强HSF-1过表达动物中观察到的表型的突变。