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Systemic, maternal and transgenerational effects of nutrient stress

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:
9552207
负责人:
Larry Ryan Baugh
金额:
$30.08万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-09-18 至 2019-08-31

项目摘要

项目成果

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中文摘要
翻译
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营养物质的可利用性如何控制 发展C.优雅线虫已经进化到能在盛宴和饥荒中生存, 或者通过控制食物供应来操纵。蠕虫还能够在细胞和组织中进行遗传分析, 有机体水平,和跨代的研究,促进了较短的世代时间。此外,缺乏 DNA甲基化表明替代的,不太了解的表观遗传机制。当幼虫在 在缺乏食物的情况下,它们可逆地抑制发育(“L1抑制”)。胰岛素样信号调节L1阻滞, daf-16/FOXO突变体是抑制缺陷型的。初步结果表明,daf-16/FOXO调节L1阻滞细胞, 非自主地,他们确定了两个保守的信号通路下游运作。这些 途径促进进食幼虫的发育,但daf-16/FOXO在饥饿期间抑制它们。胰岛素样 信号传导还介导热量限制对母体供应的影响,影响后代大小, 在饥饿恢复期间生长。L1阻滞期间的饥饿也会导致饥饿存活率增加, 耐热性以及基因表达的改变长达三代。这些令人兴奋的初步 结果表明,蠕虫可用于模拟营养胁迫对疾病风险的长期影响, 包括母体效应和表观遗传效应。这一建议的核心假设是, 影响发育生理学系统,母性和transgeneratively。这一目标 该研究的目的是确定介导这种效应的信号通路和基因调控机制。的 基本原理是使用一个理想的适合的模型系统,以确定如何发展的反应,营养胁迫 在整个动物和它的生命周期中是协调的。中心假设得到了强有力的初步支持 数据和文献。它将测试以下三个目标:1)确定daf-16/FOXO调节 信号介导发育停滞的系统控制,2)确定母体效应的机制, 热量限制对体型和饥饿恢复的影响; 3)确定表观遗传机制和效应基因 抗逆性遗传。遗传学、基因组学、细胞生物学和生物化学分析将用于 完成这些目标。初步研究中提出的主要现有菌株和表型测定将 采用这一建议是创新的发展一个简单的有机体模型的系统和长期的影响 营养压力对发育和疾病风险的影响。这项研究将是重要的,因为它将填补关键 在理解营养压力如何影响细胞行为、母体供应和遗传方面存在差距, 疾病风险。胰岛素样信号传导和其他能量稳态途径的高度保守作用 这表明,所发现的机制将是保守的。
英文摘要
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.
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Genetic and Genomic Analysis of Starvation Resistance in C. elegans
  • 批准号:
    10272834
  • 项目类别:
  • 资助金额:
    $30.46万
  • 财政年份:
    2021
  • 负责人:
    Larry Ryan Baugh
  • 依托单位:
Genetic and Genomic Analysis of Starvation Resistance in C. elegans
  • 批准号:
    10656554
  • 项目类别:
  • 资助金额:
    $30.39万
  • 财政年份:
    2021
  • 负责人:
    Larry Ryan Baugh
  • 依托单位:
Systemic, maternal and transgenerational effects of nutrient stress
  • 批准号:
    10473672
  • 项目类别:
  • 资助金额:
    $31.01万
  • 财政年份:
    2015
  • 负责人:
    Larry Ryan Baugh
  • 依托单位:
Systemic, maternal and transgenerational effects of nutrient stress
  • 批准号:
    9008873
  • 项目类别:
  • 资助金额:
    $30.08万
  • 财政年份:
    2015
  • 负责人:
    Larry Ryan Baugh
  • 依托单位:
海外基金