Epigenetic Regulation of Longevity in Response to Environmental Signals

项目摘要/摘要 一个关键问题是环境信号如何以表观遗传的方式影响健康和寿命。 信息素被包括哺乳动物在内的许多动物用来在个体之间进行交流，以及 众所周知，感应信息素会影响动物的行为，甚至影响动物的健康。在无脊椎动物中，这些 最近发现，个体之间的信息素相互作用是调节寿命的一种手段。我们 研究发现，在线虫(两性)中，雄性信息素缩短了异性的寿命。 令人兴奋的是，我的初步数据表明，男性信息素的化学感觉增加了表达 一种保守的染色质修饰物(H3K27me3去甲基酶UTX-1)。重要的是 UTX-1水平的变化似乎在调节长寿方面具有重要的功能；敲除UTX-1 在男性在场和不在场的情况下，延长寿命并提高抗应激能力。总而言之，这些数据 建议一个模型，在该模型中，染色质景观的变化改变了动物的寿命，以应对 雄性信息素。提出的研究的首要目标是获得一种机械性的 了解染色质修饰剂如何调节寿命以响应环境信号。 这项建议使用了一个高度易处理的线虫模型系统来理解环境信号如何 例如，信息素会影响染色质修饰物和寿命。这项提案将结合使用 遗传学、基于RNAi的筛选和基因组学方法来揭示染色质的分子机制-- 以及信息素介导的长寿调节。重要的是，许多关键的长寿途径和基因 在线虫和哺乳动物之间非常保守，包括染色质修饰物上调 信息素(UTX-1)。信息素可以调节哺乳动物寿命这一诱人的想法还没有 由于哺乳动物个体间交流的复杂性，我进行了严格的测试，我在 线虫应该为未来对哺乳动物的研究奠定基础。此外，我提出的研究 应该对染色质的作用有基本的见解，对长寿的调节可能会有 对人类健康、寿命和寿命的影响。 这项建议建立在我以前研究经验的基础上，并将为我提供技术和智力方面的 培训让我为独立调查员的职业生涯做好准备。我的主要导师安妮·布鲁内特博士，还有 共同导师汤姆·兰多博士将提供重要的科学和职业指导，以确保我的成功。我的 顾问和合作者补充了Brunet博士和Rando博士的专业知识，并将帮助我实现我的职业生涯 和研究目标。我将在指导K99期间接受的科学和职业发展培训 这个奖项的阶段将极大地增强我目前的职业和研究轨迹，并将使我成为一个 竞争激烈的顶尖研究机构教员职位的候选人。

Project Summary/Abstract A key question is how environmental signals influence health and lifespan in an epigenetic manner. Pheromones are used by many animals, including mammals, to communicate between individuals, and sensing pheromones is known to impact the behavior and even the health of animals. In invertebrates, these inter-individual, pheromone interaction have recently been found to be a means of regulating longevity. We have found that male pheromones shorten the lifespan of the opposite sex in C. elegans (the hermaphrodite). Excitingly, my preliminary data suggests that chemosensation of male pheromones increases the expression of a conserved chromatin modifier (the H3K27me3 demethylase UTX-1) in hermaphrodites. Importantly, changes in utx-1 levels seem to be functionally important in the regulation of longevity; knock-down of utx-1 extends lifespan and promotes stress resistance in the presence and absence of males. Together, these data suggest a model in which changes in the chromatin landscape alter the longevity of an animal in response to male pheromones. The overarching goal of the proposed research is to gain a mechanistic understanding of how chromatin modifiers regulate longevity in response to environmental signals. This proposal uses a highly tractable C. elegans model system to understand how an environmental signal such as pheromones impacts chromatin modifiers and longevity. This proposal will use a combination of genetics, RNAi-based screens, and genomic approaches to uncover the molecular mechanism of chromatin- and pheromone-mediated regulation of longevity. Importantly, many key longevity pathways and genes are well conserved between C. elegans and mammals, including the chromatin modifier upregulated by pheromones (utx-1). The tantalizing idea that pheromones could regulate mammalian longevity has not yet been tested rigorously due to the complexity of inter-individual communication in mammals, and my studies in C. elegans should lay the foundation for future studies in mammals. Furthermore, my proposed research should yield fundamental insights into the role of chromatin the regulation of longevity that will likely have implications for human healthspan and longevity. This proposal builds on my previous research experience and will provide me with technical and intellectual training to prepare me for a career as an independent investigator. My primary mentor, Dr. Anne Brunet, and co-mentor, Dr. Tom Rando, will provide important scientific and career guidance to ensure my success. My advisors and collaborators complement Drs. Brunet and Rando's expertise and will help me reach my career and research goals. The scientific and career development training I will receive during the mentored K99 phase of this award will substantially enhance my current career and research trajectory and will make me a highly competitive candidate for faculty positions at top tier research institutes.