Systemic, maternal and transgenerational effects of nutrient stress

营养胁迫的系统性、母性和跨代影响

• 批准号: 10473672
• 负责人: Larry Ryan Baugh
• 金额: $ 31.01万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10473672
• 关键词: Adult; Affect; Animals; Biochemical; Buffers; Caenorhabditis elegans; Cancer Etiology; Cell Death; Data; Development; Diabetes Mellitus; Diet; Disease; Epigenetic Process; Famines; Fertility; Food; Foundations; Gene Expression; Generations; Genetic; Genets; Genomics; Germ Lines; Goals; Growth; Health; Insulin; Iron; Knowledge; Larva; Life; Lipid Peroxidation; Lipids; Literature; Longevity; Longitudinal Studies; Mediating; Modeling; Molecular; Nematoda; Nutrient; Oocytes; Outcome; Pathologic; Pathway interactions; Penetrance; Pharmacology; Physiology; Prevention strategy; Public Health; Regulation; Regulator Genes; Research; Resistance; Signal Transduction; Small RNA; Starvation; Stress; System; Testing; Therapeutic Intervention; Time; Tumor Suppression; Tumor Suppressor Proteins; Work; detection of nutrient; dietary restriction; disorder risk; emerging adult; epigenetic memory; fitness; human disease; innovation; intergenerational; mother nutrition; nutrition; reproductive success; response; stress management; transcription factor; transmission process; tumor

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.

项目摘要 对营养应力的发展反应反映了系统级调节 - 整个动物及其后代 可能受到影响。但是，在整个动物和几代人之间如何协调发育生理学是如何的 不太了解。该项目的长期目标是了解持续效应的分子基础 round虫秀丽隐杆线虫中的营养应激。蠕虫是理想的模型，因为它已经发展为繁荣 盛宴和饥荒及其短期时间促进了多代研究。初步结果显示 这种幼虫饥饿会导致成年初期种系肿瘤（肾上腺内作用），但 减少胰岛素/IGF信号传导通过促进铁铁作用来抑制肿瘤。他们还表明， NAL饮食限制可通过减少胰岛素/IGF信号传导（间间 世代效应）。我们的研究还证明了饥饿耐药性增加的表观遗传遗传 Dauer停滞后的生命周期以及基因表达改变（转世效应），并且 病因中的小RNA介导了这些作用。这些初步结果为 营养应激在发育和跨几代人中持续影响的机械分析。这 这一提议的前提是，早期饥饿损害了发展的完整性，但父母或一个人 时离养分应力缓冲饥饿的后代。中心假设是早期饥饿的铅 开发成人种系肿瘤，但孕产妇的供应和表观遗传遗传保护后代 从饥饿的这种病理作用中。这些目标是识别信号传导和基因调节机甲 - 介导对世代相传的营养应激的适应性的障碍。中心假设得到 强大的初步数据以及文献。它将通过以下三个目的对其进行测试：1）确定机甲 - 减少胰岛素/IGF信号传导抑制饥饿诱导的种系肿瘤的障碍，2） 孕产妇饮食限制使后代从早期生命的病理作用缓冲后代的机制 3）确定介导饥饿耐药性表观遗传遗传的调节机制。基因 IC，基因组，药理和生化方法将用于完成这些目标。这项工作是 创新的模型创新，以促进内部，间和转世EF-机械分析 养分胁迫的效果和用于研究铁毒性作为肿瘤抑制剂机制 转录因子和胰岛素/IGF信号传导。拟议工作的贡献将是确定 介导对世代相传营养应激的适应的调节机制。这些包括机械 FOXO转录因子抑制肿瘤的nisms以及饥饿遗传的机制 反抗。这些贡献将是重要的，因为它们将填补了解如何理解如何 营养应力会影响发育，孕产妇配置和表观遗传遗传。深处保守 胰岛素/IGF信号传导和FOXO因子的功能表明，发现的机制将是保守的。

项目成果

Insulin-like signalling to the maternal germline controls progeny response to osmotic stress.

• DOI: 10.1038/ncb3470
• 发表时间: 2017-03
• 期刊: Nature cell biology
• 影响因子: 21.3
• 作者: Burton NO;Furuta T;Webster AK;Kaplan RE;Baugh LR;Arur S;Horvitz HR
• 通讯作者: Horvitz HR

Pervasive Positive and Negative Feedback Regulation of Insulin-Like Signaling in Caenorhabditis elegans.

秀丽隐杆线虫中胰岛素样信号传导的普遍正反馈和负反馈调节。

• DOI: 10.1534/genetics.118.301702
• 发表时间: 2019
• 期刊: Genetics
• 影响因子: 3.3
• 作者: Kaplan,RebeccaEW;Maxwell,ColinS;Codd,NicoleKurhanewicz;Baugh,LRyan
• 通讯作者: Baugh,LRyan

Correction: Maternal Diet and Insulin-Like Signaling Control Intergenerational Plasticity of Progeny Size and Starvation Resistance.

• DOI: 10.1371/journal.pgen.1007639
• 发表时间: 2018-08
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Hibshman JD;Hung A;Baugh LR
• 通讯作者: Baugh LR

Food perception without ingestion leads to metabolic changes and irreversible developmental arrest in C. elegans.

没有摄入的食物感知会导致秀丽隐杆线虫的代谢变化和不可逆的发育停滞。

• DOI: 10.1186/s12915-018-0579-3
• 发表时间: 2018
• 期刊: BMC biology
• 影响因子: 5.4
• 作者: Kaplan,RebeccaEW;Webster,AmyK;Chitrakar,Rojin;Dent,JosephA;Baugh,LRyan
• 通讯作者: Baugh,LRyan

Population Selection and Sequencing of Caenorhabditis elegans Wild Isolates Identifies a Region on Chromosome III Affecting Starvation Resistance.

秀丽隐杆线虫野生分离株的群体选择和测序确定了影响饥饿抵抗的 III 号染色体区域。

• DOI: 10.1534/g3.119.400617
• 发表时间: 2019
• 期刊: G3 (Bethesda, Md.)
• 作者: Webster,AmyK;Hung,Anthony;Moore,BradT;Guzman,Ryan;Jordan,JamesM;Kaplan,RebeccaEW;Hibshman,JonathanD;Tanny,RobynE;Cook,DanielE;Andersen,Erik;Baugh,LRyan
• 通讯作者: Baugh,LRyan