Regulation of Heat Shock Transcription Factor in Long-lived Animals

描述（由申请人提供）：遗传学研究清楚地表明，衰老的速度，像许多其他生物过程一样，是受调节的。我们之前的研究结果表明，秀丽隐杆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，它与胰岛素/ igf -1样信号网络协同作用，调节衰老速度和年龄相关疾病的发生。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对抗年龄相关疾病的新治疗策略。我们认为HSF-1在影响寿命的DAF-2胰岛素/ igf -1样信号网络中起着至关重要的作用。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daf-2突变延长寿命需要HSF-1活性。我们最近的研究结果表明，HSF-1的活性与DAF-16一样，可以由DAF-2胰岛素/ igf -1样信号直接调节。此外，我们还发现了两个新的基因ddl-1和ddl-2，它们可能通过负向调节HSF-1活性来影响寿命。基于这些观察结果，本研究将重点关注：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途径的其他组分相互作用。2)鉴定了可能在HSF-1通路中起决定寿命作用的两个新的长寿基因ddl-1和ddl-2。我们将研究HSF-1的活性是否受ddl-1和ddl-2的调节，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在何时何地起调节寿命的作用。3)通过蛋白-蛋白相互作用确定可调节HSF-1活性的蛋白。以往对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)确定HSF-1通路中调控衰老速率和抗逆性的其他基因。我们将进行遗传筛选，以确定可以抑制或增强在hsf-1过表达动物中观察到的表型的突变。

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.