Systemic, maternal and transgenerational effects of nutrient stress

项目总结 对营养胁迫的发育反应反映了系统水平的调节--整个动物及其后代 可能会受到影响。但发育生理学是如何在动物之间和世代之间协调的 不是很清楚。这个项目的长期目标是了解营养供应是如何支配的。 发展。线虫已经进化到可以在盛宴和饥荒中幸存下来，而发育可以停止、开始 并以其他方式通过控制食物供应来操纵。蠕虫还使细胞和细胞的遗传分析成为可能 通过较短的世代时间，生物体水平和跨代研究都得到了促进。此外，缺乏 DNA甲基化暗示了另一种但鲜为人知的表观遗传机制。当幼虫在海里孵化时 缺乏食物，他们可逆地阻碍了发育(“一级逮捕”)。胰岛素样信号调节L1停滞，并且 DAF-16/FOXO突变体是有滞留缺陷的。初步实验结果表明，daf-16/FOXO对L1期阻滞细胞有调节作用。 非自主的，他们确定了在其下游运行的两条保守的信号通路。这些 途径促进摄食幼虫的发育，但DAF-16/FOXO在饥饿期间抑制它们。胰岛素样物质 信号也调节热量限制对母体供应的影响，影响后代的大小和 饥饿恢复期间的生长。L1捕获期间的饥饿也会导致饥饿存活率增加和 耐热性以及长达三代的基因表达变化。这些激动人心的预赛 结果表明，这种蠕虫可以用来模拟营养压力对疾病风险的长期影响， 包括母体效应和表观遗传效应。这一提议的中心假设是营养胁迫 对发育生理学有系统、母性和跨代的影响。这样做的目的是 建议确定介导这种影响的信号通路和基因调控机制。这个 基本原理是使用一个理想的模型系统来确定发育对营养胁迫的反应 在动物和它的生命周期中是协调的。中心假说得到了强有力的初步支持 数据和文献一样。它将进行以下三个目标的测试：1)识别DAF-16/FOXO调节的 调节发育停滞的系统控制的信号，2)确定母体效应的机制 卡路里限制大小和饥饿恢复和3)确定表观遗传机制和效应基因 抗逆性遗传。遗传、基因组、细胞生物学和生化分析将用于 完成这些目标。初步研究中提出的主要现有菌株和表型分析将是 使用。这一建议在开发系统和长期影响的简单生物模型方面具有创新性。 营养压力对发育和疾病风险的影响。这项研究将具有重要意义，因为它将填补关键 对营养应激如何影响细胞行为、母体供应和遗传的理解存在差距 疾病风险。胰岛素样信号和其他能量稳态通路的高度保守作用 这表明已发现的机制将是保守的。

PROJECT SUMMARY Developmental responses to nutrient stress reflect systems-level regulation -- the entire animal and its progeny can be affected. But how developmental physiology is coordinated across the animal and over generations is not well understood. The long-term goal of this project is to understand how nutrient availability governs development. C. elegans has evolved to survive feast and famine, and development can be stopped, started and otherwise manipulated by controlling food supply. Worms also enable genetic analysis at the cellular and organismal levels, and transgenerational studies are facilitated by short generation time. Furthermore, lack of DNA methylation suggests alternative, less understood epigenetic mechanisms. When larvae hatch in the absence of food they reversibly arrest development (`L1 arrest'). Insulin-like signaling regulates L1 arrest, and daf-16/FOXO mutants are arrest-defective. Preliminary results show that daf-16/FOXO regulates L1 arrest cell- nonautonomously, and they identify two conserved signaling pathways operating downstream of it. These pathways promote development in fed larvae, but daf-16/FOXO represses them during starvation. Insulin-like signaling also mediates effects of caloric restriction on maternal provisioning, affecting progeny size and growth during starvation recovery. Starvation during L1 arrest also causes increased starvation survival and heat resistance as well as altered gene expression for up to three generations. These exciting preliminary results suggest that the worm can be used to model long-term effects of nutrient stress on disease risk, including both maternal and epigenetic effects. The central hypothesis of this proposal is that nutrient stress affects developmental physiology systemically, maternally and transgenerationally. The objectives of this proposal are to identify signaling pathways and gene regulatory mechanisms that mediate such effects. The rationale is to use an ideally suited model system to determine how developmental responses to nutrient stress are coordinated across the animal and its lifecycle. The central hypothesis is supported by strong preliminary data as well as the literature. It will be tested with the following three aims: 1) identify daf-16/FOXO-regulated signals mediating systemic control of developmental arrest, 2) identify mechanisms for maternal effects of caloric restriction on size and starvation recovery and 3) identify epigenetic mechanisms and effector genes for inheritance of stress resistance. Genetic, genomic, cell biological and biochemical analyses will be used to complete these aims. Primarily existing strains and phenotypic assays presented in preliminary studies will be used. This proposal is innovative for developing a simple organismal model of systemic and long-term effects of nutrient stress on development and disease risk. This research will be significant because it will fill critical gaps in understanding of how nutrient stress affects cellular behavior, maternal provisioning and inheritance of disease risk. The deeply conserved role of insulin-like signaling and other energy homeostasis pathways suggests that the mechanisms discovered will be conserved.