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: 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/9552207
• 关键词: Acute; Affect; Animals; Area; Behavior; 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; Gene-Modified; Generations; Genes; Genetic; Genetic Models; Genomics; Goals; Growth; Health; Heritability; Homeostasis; Insulin; Intervention; Investigation; Larva; Link; Literature; Long-Term Effects; Malignant Neoplasms; Malnutrition; Mediating; Modeling; Molecular; Nematoda; Nutrient; Nutritional; Outcome; Pathway interactions; Phenotype; Physiology; Prevention strategy; Property; Public Health; RNA Interference; Recovery; Regulation; Regulator Genes; Research; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Protein; Small RNA; Starvation; Stem cells; Stress; System; Testing; Therapeutic Intervention; Time; Transforming Growth Factor beta; Work; cancer risk; disorder risk; genetic analysis; 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养分可用性如何管理 发展。秀丽隐杆线虫已经进化为在盛宴和饥荒中生存，可以制止发展，开始 否则通过控制食物供应来操纵。蠕虫还可以在细胞和 有机水平和跨代研究是通过短期生成时间促进的。此外，缺乏 DNA甲基化提出了替代性，较少了解的表观遗传机制。幼虫在 他们没有食物可逆地逮捕发展（“ L1逮捕”）。胰岛素样信号传导调节L1逮捕，并 DAF-16/FOXO突变体是逮捕缺陷的。初步结果表明，DAF-16/FOXO调节L1阻滞细胞 - 非自主，他们确定了两个保守的信号通路，其下游运行。这些 途径促进了喂养幼虫的发展，但DAF-16/Foxo在饥饿期间压抑了它们。类似胰岛素 信号传导还介导了热量限制对母体配置的影响，影响后代的大小和 饥饿恢复期间的生长。 L1停滞期间的饥饿还会导致饥饿的存活增加，并且 耐热性和基因表达改变多达三代人。这些令人兴奋的初步 结果表明，蠕虫可用于模拟营养应激对疾病风险的长期影响， 包括母体和表观遗传效应。该提议的中心假设是营养应激 在系统，母体和转发上影响发育生理。目标的目标 建议是确定介导此类作用的信号通路和基因调节机制。这 理由是使用理想适合的模型系统来确定对养分压力的发展反应 在动物及其生命周期中进行协调。中心假设得到了强大的初步支持 数据和文献。它将通过以下三个目标进行测试：1）识别DAF-16/FOXO调节 信号介导了对发育停滞的全身控制的信号，2）确定孕产妇影响的机制 对大小和饥饿恢复的热量限制，3）确定表观遗传机制和效应基因 压力抵抗的继承。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。该提案具有创新的，用于开发系统性和长期影响的简单生物模型 营养压力对发育和疾病风险。这项研究将是重要的，因为它将填补关键 了解营养应激如何影响细胞行为，母体供应和继承的差距 疾病风险。胰岛素样信号传导和其他能量稳态途径的深刻保守作用 表明发现的机制将得到保存。