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

基本信息

批准号：
10624328
负责人：
SARAH E HALL
金额：
$ 30万
依托单位：
SYRACUSE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-17 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624328
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 Experimental Genetics 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 Proliferating 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 comparison control 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 posttranscriptional sensor steroid hormone transgenerational epigenetic inheritance

项目摘要

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，胎儿和儿童时期经历会影响人类的成人疾病组织特异性基因表达状态的变化和神经内分泌HPA的功能持续变化轴。但是，环境提示在子宫或幼儿期间经历的分子途径导致与成人疾病相关的长期影响，以及它们如何在世代上遗传，是不太了解。秀丽隐杆线虫线虫线虫提供了独特的动物模型系统，以探索该模型由于早期经验而导致的基因表达的环境编程机制。虽然成人在发育外观早期经历环境压力的动物与动物完全相同经历了有利的条件，这些成年人保留了对环境历史的蜂窝记忆由于特定的压力而异，其基因表达和生育能力的变化表现出来。与对照组相比取决于组成的内分泌信号通路和CSR-1 RNAi途径的上调。有趣的是，这些内分泌信号传导途径，类固醇骑马信号传导和脂肪酸代谢是在缺乏种系的长寿动物中也被上调。另外，降低的生育表型饥饿压力的动物也通过HRDE-1 RNAi途径至少遗传了两代。该提案的总体目标是研究如何促进无系寿命的途径动物还可以调节经历营养应激的动物的繁殖。这个特定的目的建议包括：1）研究类固醇信号传导和脂肪酸代谢在调节中的作用早年饥饿后的生育能力。此目的建议遗传和生化实验来检验假设 DAF-12/NHR充当“脂肪传感器”，以根据储存脂肪的水平调节生殖系的生产直接调节基因具有促进种系增殖开始的功能。 2）使用生化并开发遗传学实验，测试CSR-1降压器中脂肪酸代谢增加的增加成人是由于CSR-1在肠道中直接调节脂肪基因，或者是由于生育率降低的间接作用在CSR-1低描绘中，由于生殖线缺陷可能触发这些途径。 3）确定机制降低经历营养压力的动物进展的生育能力降低的遗传。实验将测试在F1后代，类固醇信号传导和脂肪酸代谢基因是否也更新。 HRDE-1 相关的siRNA也将在后代进行深度测序，以鉴定有助于促成靶基因降低的生育表型。这些实验将共同研究如何促进躯体的途径无种系动物的寿命也可以调节由于早期饥饿而调节生育能力，以及RNAi如何途径有助于代谢编程的继承。