Characterization of endocrine signaling and RNAi pathways as mechanisms regulating environmental programming in C. elegans

内分泌信号传导和 RNAi 途径作为调节秀丽隐杆线虫环境编程机制的表征

• 批准号: 10409696
• 负责人: SARAH E HALL
• 金额: $ 30万
• 依托单位: SYRACUSE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-17 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409696
• 关键词: Adult; Animal Model; Animals; Barker Hypothesis; Biochemical; Biochemical Genetics; Biological Models; Caenorhabditis elegans; Candidate Disease Gene; Childhood; Cues; Data; Defect; Development; Disease; Endocrine; Exhibits; FAT gene; Famines; Fatty Acids; Fatty acid glycerol esters; Fertility; Fetus; Gene Expression; Gene Targeting; Generations; Genes; Genetic; Genetic Transcription; Germ Cells; Germ Lines; Goals; Health; Human; Hypothalamic structure; Individual; Inherited; Intestines; Investigation; Life; Longevity; Low Birth Weight Infant; Mediating; Memory; Messenger RNA; Metabolic; Molecular; Nematoda; Neurosecretory Systems; Nuclear; Nutritional; Obesity; Oleic Acids; Outcome; Parents; Pathway interactions; Phenotype; Physiology; Pituitary-Adrenal System; Production; RNA Binding; RNA Interference; Recording of previous events; Regulation; Reproduction; Rodent Model; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Small RNA; Starvation; Sterility; Steroids; Stress; System; Testing; Tissue-Specific Gene Expression; Untranslated RNA; Up-Regulation; Work; base; developmental genetics; early childhood; early experience; epigenetic regulation; experience; experimental study; fatty acid metabolism; fetal; gene function; hormonal signals; human model; in utero; mature animal; sensor; steroid hormone; transgenerational epigenetic inheritance

Increasing evidence suggests that fetal and childhood experiences impact adult disease in humans through changes in tissue-specific gene expression states and sustained altered function of the neuroendocrine HPA axis. However, the molecular pathways by which environmental cues experienced in utero or early childhood result in long-lasting effects associated with adult disease, and how they can be inherited over generations, are not well understood. Caenorhabditis elegans nematodes provide a unique animal model system in which to explore the mechanisms of environmental programming of gene expression due to early experience. Although adult animals that experienced environmental stress early in development appear grossly identical to animals that experienced favorable conditions, these adults retain a cellular memory of their environmental history that is manifested by changes in gene expression and fertility that are distinct for the particular stress experienced. Animals that experienced early-life starvation exhibited decreased fertility compared to controls, which is dependent upon the upregulation of conserved endocrine signaling pathways and the CSR-1 RNAi pathway. Interestingly, these endocrine signaling pathways, steroid hormone signaling and fatty acid metabolism, are also upregulated in long-lived animals lacking a germ line. In addition, the reduced fertility phenotype of starvation-stressed animals is also inherited for at least two generations via the HRDE-1 RNAi pathway. The overall goal of this proposal is to investigate how pathways that can promote longevity in germline-less animals can also modulate reproduction in animals that experienced nutritional stress. The specific aims of this proposal include: 1) investigate the roles of steroid signaling and fatty acid metabolism in the regulation of fertility after early-life starvation. This aim proposes genetic and biochemical experiments to test the hypothesis that DAF-12/NHR acts as a “fat sensor” to modulate germ line production based on levels of stored fat by directly regulating gene(s) with functions in promoting the onset of germline proliferation. 2) Using biochemical and developmental genetics experiments, test whether the increased fatty acid metabolism in csr-1 hypomorph adults is due to direct regulation of fat genes by CSR-1 in the intestine, or an indirect effect of reduced fertility in the csr-1 hypomorph, as germ line defects may trigger these pathways. 3) Determine the mechanisms of inheritance for reduced fertility in progeny of animals that experienced nutritional stress. Experiments will test whether steroid signaling and fatty acid metabolism genes are also upregulated in F1 progeny. HRDE-1 associated siRNAs will also be deep sequenced in the progeny to identify target genes contributing to the reduced fertility phenotype. Together, these experiments will investigate how pathways that promote somatic longevity in germline-less animals can also modulate fertility due to early life starvation, and how RNAi pathways contribute to inheritance of metabolic programming.

越来越多的证据表明，胎儿和童年的经历通过以下途径影响人类的成人疾病 组织特异性基因表达状态的变化与神经内分泌HPA功能的持续性改变 轴心。然而，环境线索在子宫或儿童早期经历的分子途径 导致与成人疾病相关的长期影响，以及它们如何代代相传，是 不是很清楚。 秀丽线虫提供了一种独特的动物模型系统，可以在其中探索 由于早期经验，环境编程基因表达的机制。虽然是成年人 在发育早期经历环境压力的动物看起来与那些 经历了有利的条件后，这些成虫保留了对其环境历史的细胞记忆，即 表现为基因表达和生育力的变化，这与所经历的特定压力是不同的。 与对照组相比，经历早期饥饿的动物表现出生育力下降，这是 依赖于保守的内分泌信号通路和CSR-1 RNAi通路的上调。 有趣的是，这些内分泌信号通路，类固醇激素信号和脂肪酸代谢，是 在缺乏生殖系的长寿动物中也表达上调。此外，生育力下降的表型 饥饿应激动物也通过HRDE-1 RNAi途径遗传至少两代。 这项提议的总体目标是调查如何在无生殖系的人中促进长寿的途径 动物也可以调节经历了营养压力的动物的繁殖。这样做的具体目的是 建议包括：1)研究类固醇信号和脂肪酸代谢在调节 早年饥饿后的生育能力。这一目标提出了用遗传和生化实验来验证这一假说。 DAF-12/NHR起到了“脂肪传感器”的作用，根据储存的脂肪水平，通过 直接调控基因(S)具有促进生殖系开始增殖的功能。2)使用生物化学 和发育遗传学实验，测试CSR-1低晶型脂肪酸代谢是否增加 成人是由于肠道中CSR-1对脂肪基因的直接调节，或者是生育力下降的间接影响 在CSR-1低晶型中，AS生殖系缺陷可能触发这些通路。3)确定 经历营养压力的动物后代生育力下降的遗传。实验将测试 类固醇信号和脂肪酸代谢基因在F1代中是否也上调。HRDE-1 相关的siRNA也将在后代中进行深度测序，以确定与 生育能力下降的表型。这些实验将共同研究促进体细胞生长的途径 无生殖系动物的寿命也可以由于早期的生命饥饿而调节生育能力，以及RNAi是如何 途径有助于代谢编程的遗传。