Systemic, maternal and transgenerational effects of nutrient stress

项目摘要 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 会受到影响。但是发育生理学是如何在动物之间和几代人之间协调的， 没有被很好地理解。这个项目的长期目标是了解持续效应的分子基础 线虫C.优雅蠕虫是一个理想的模型，因为它已经进化到在 盛宴和饥荒，它的短世代时间有利于多代研究。初步结果显示 幼虫饥饿导致生殖系肿瘤在成年早期发展（代内效应），但 胰岛素/IGF信号的减少通过促进铁凋亡来抑制肿瘤。他们还表示，mater- 最终的饮食限制通过减少胰岛素/IGF信号传导（inter-insulin/IGF signaling）来保护后代免受饥饿诱导的肿瘤。 世代效应）。我们的研究还证明了增加饥饿抗性的表观遗传 和寿命以及dauer停滞后改变的基因表达（跨代效应），他们建议- 生殖细胞系中小RNA介导了这些效应。这些初步成果为 营养胁迫在发育过程中和跨代持续影响的机制分析。的 这一建议的前提是，早期生活饥饿损害发育的完整性，但父母或一个- 侧营养胁迫缓冲后代免于饥饿。核心假设是早期的饥饿导致 成年生殖系肿瘤的发展，但母亲提供和表观遗传保护后代 免受饥饿的病理影响目的是鉴定信号传导和基因调控机制， 在几代人之间调节对营养压力的适应的基因。中心假设得到了以下方面的支持： 强大的初步数据以及文献。它将测试以下三个目标：1）识别mech- 胰岛素/IGF信号传导减少抑制饥饿诱导的种系肿瘤的机制，2）识别 母体饮食限制缓冲后代免受早期饥饿病理影响的机制， 3）确定调节饥饿抗性表观遗传的调控机制。Genet- 将采用基因组学、药理学和生物化学方法来完成这些目标。这项工作是 创新性地开发模型，促进对代内、代间和代间影响力的机制分析， 营养应激的影响和研究作为FoxO调节的肿瘤抑制机制的铁凋亡 转录因子和胰岛素/IGF信号传导。拟议工作的贡献将是确定 调节机制，调解适应跨代营养压力。其中包括机械- FoxO转录因子抑制肿瘤的机制以及饥饿遗传机制 阻力这些贡献将是重要的，因为它们将填补理解如何实现这一目标的关键空白。 营养压力影响发育、母体供给和表观遗传。深保守的 胰岛素/IGF信号传导和FoxO因子的功能表明所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 the molecular basis of persistent effects of nutrient stress in the roundworm C. elegans. The worm is an ideal model since it has evolved to thrive in feast and famine and its short generation time facilitates multigenerational studies. Preliminary results show that larval starvation causes germline tumors to develop during early adulthood (intragenerational effect), but that reduction of insulin/IGF signaling suppresses tumors by promoting ferroptosis. They also show that mater- nal dietary restriction protects progeny from starvation-induced tumors by reducing insulin/IGF signaling (inter- generational effect). Our studies also demonstrate epigenetic inheritance of increased starvation resistance and lifespan as well as altered gene expression following dauer arrest (transgenerational effect), and they sug- gest that small RNAs in the germ line mediate these effects. These preliminary results lay the foundation for mechanistic analysis of persistent effects of nutrient stress during development and across generations. The premise of this proposal is that early-life starvation compromises developmental integrity, but parental or an- cestral nutrient stress buffers progeny from starvation. The central hypothesis is that early-life starvation leads to development of adult germline tumors, but maternal provisioning and epigenetic inheritance protect progeny from such pathological effects of starvation. The objectives are to identify signaling and gene regulatory mech- anisms that mediate adaptation to nutrient stress across generations. 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 mech- anisms by which reduction of insulin/IGF signaling suppresses starvation-induced germline tumors, 2) Identify mechanisms by which maternal dietary restriction buffers progeny from pathological effects of early-life starva- tion, and 3) Identify regulatory mechanisms that mediate epigenetic inheritance of starvation resistance. Genet- ic, genomic, pharmacological and biochemical approaches will be used to complete these aims. This work is innovative for developing models that facilitate mechanistic analysis of intra-, inter- and transgenerational ef- fects of nutrient stress and for investigating ferroptosis as a tumor suppressor mechanism regulated by a FoxO transcription factor and insulin/IGF signaling. The contributions of the proposed work will be identification of regulatory mechanisms that mediate adaptation to nutrient stress across generations. These include mecha- nisms by which FoxO transcription factors suppress tumors as well as mechanisms for inheritance of starvation resistance. These contributions will be significant because they will fill critical gaps in understanding of how nutrient stress affects development, maternal provisioning, and epigenetic inheritance. The deeply conserved function of insulin/IGF signaling and FoxO factors suggests that mechanisms discovered will be conserved.