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持续性效应的分子基础。 线虫体内营养胁迫的研究。蠕虫是一个理想的模型，因为它已经进化到在 盛宴和饥荒及其短暂的世代时间为多代研究提供了便利。初步结果显示 幼虫饥饿会导致生殖系肿瘤在成年早期发展(代内效应)，但 胰岛素/胰岛素样生长因子信号的减少通过促进铁下垂来抑制肿瘤。它们还表明，物质- Nal饮食限制通过减少胰岛素/IGF信号转导(INT)保护子代免受饥饿诱导的肿瘤 世代效应)。我们的研究还表明，表观遗传增强了抗饥性。 和寿命以及达尔被捕后基因表达的变化(跨代效应)，它们提示- 假设生殖系中的小RNA参与了这些效应的调节。这些初步结果奠定了以下基础 营养胁迫在发育期间和世代间持续影响的机理分析。这个 这一提议的前提是，早期饥饿损害了发育完整性，但父母或- 原始营养压力可以缓冲后代免受饥饿的伤害。中心假说是早期的饥饿导致 与成人生殖系肿瘤的发展有关，但母体供应和表观遗传保护后代 免受饥饿的病理性影响。其目标是确定信号和基因调控机制-- 代际间调节对营养胁迫的适应的反常现象。中心假说得到以下支持 强劲的初步数据和文献。它将以以下三个目标进行测试：1)识别机械- 胰岛素/胰岛素样生长因子信号降低抑制饥饿诱导的生殖系肿瘤，2)鉴定 母亲饮食限制缓冲后代免受早期饥饿的病理影响的机制-- 以及3)确定调节饥饿抗性表观遗传的调控机制。吉内特- 将使用IC、基因组学、药理学和生化方法来实现这些目标。这项工作是 创新地开发模型，促进代内、代间和跨代影响的机制分析 营养应激的影响及铁下垂作为FoxO调控的肿瘤抑制机制的研究 转录因子与胰岛素/胰岛素样生长因子信号传导。拟议工作的贡献将是确定 调节世代间对营养胁迫适应的调节机制。其中包括机械- FoxO转录因子抑制肿瘤的机制及饥饿遗传机制 抵抗。这些贡献将是重要的，因为它们将填补理解如何 营养应激影响发育、母体供应和表观遗传。高度保守的人 胰岛素/IGF信号转导和FoxO因子的功能表明，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 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.