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: 9008873
• 负责人: Larry Ryan Baugh
• 金额: $ 30.08万
• 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 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9008873
• 关键词: Affect; Animals; Area; Biochemical; Biological; Biological Assay; Biological Models; Caenorhabditis elegans; Caloric Restriction; Cancer Etiology; Cardiovascular Diseases; Cell physiology; Cells; DNA Methylation; Data; Development; Diabetes Mellitus; Disease; Epigenetic Process; Famines; Food; Food Supply; Gene Expression; Generations; Genes; Genetic; Genetic Models; Genomics; Goals; Growth; Health; Heating; Homeostasis; Insulin; Investigation; Larva; Link; Literature; Long-Term Effects; Malignant Neoplasms; Malnutrition; Maternal Behavior; Mediating; Modeling; Molecular; Nematoda; Nutrient; Nutritional; Outcome; Pathway interactions; Physiology; Prevention strategy; Property; Public Health; RNA Interference; Recovery; Regulation; Research; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Pathway Gene; Small RNA; Staging; Starvation; Stem Cell Development; Stress; System; Testing; Therapeutic Intervention; Time; Transforming Growth Factor beta; Work; cancer risk; disorder risk; feeding; genetic analysis; hatching; histone modification; innovation; migration; mutant; novel diagnostics; nutrition; programs; response; steroid hormone

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.

项目概要 对营养应激的发育反应反映了系统层面的调节——整个动物及其后代 可能会受到影响。但发育生理学如何在整个动物和几代人之间协调是未知的 不太理解。该项目的长期目标是了解养分可用性如何控制 发展。线虫已经进化到能够在盛宴和饥荒中生存，并且可以停止、开始发育 以及通过控制食品供应来操纵。蠕虫还可以对细胞和细胞进行遗传分析 较短的世代时间促进了有机水平和跨代研究。此外，缺乏 DNA 甲基化表明了另一种尚不为人所知的表观遗传机制。当幼虫孵化于 缺乏食物，它们会可逆地抑制发育（“L1 抑制”）。胰岛素样信号传导调节 L1 停滞，并且 daf-16/FOXO 突变体是逮捕缺陷的。初步结果表明daf-16/FOXO调节L1细胞阻滞- 非自主地，它们识别出在其下游运行的两条保守的信号通路。这些 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。类胰岛素 信号传导还介导热量限制对母体供给的影响，影响后代的大小和 饥饿恢复期间的生长。 L1 逮捕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最多可达三代。这些激动人心的预赛 结果表明，该蠕虫可用于模拟营养应激对疾病风险的长期影响， 包括母体效应和表观遗传效应。该提案的中心假设是营养胁迫 系统地、母性地和跨代地影响发育生理学。本次活动的目标 建议确定介导此类效应的信号通路和基因调控机制。这 基本原理是使用一个非常适合的模型系统来确定发育对营养胁迫的反应 在整个动物及其生命周期中进行协调。中心假设得到强有力的初步支持 数据以及文献。它将针对以下三个目标进行测试：1）识别 daf-16/FOXO 监管的 介导发育停滞系统控制的信号，2）确定母体影响的机制 对体型和饥饿恢复的热量限制，3) 确定表观遗传机制和效应基因 抗压能力的遗传。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测定将是 用过的。该提案对于开发系统性和长期影响的简单生物模型具有创新性 营养胁迫对发育和疾病风险的影响。这项研究意义重大，因为它将填补关键 对营养应激如何影响细胞行为、母体供给和遗传的理解存在差距 疾病风险。胰岛素样信号传导和其他能量稳态途径的深层保守作用 表明所发现的机制将被保留。