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，胎儿和儿童时期的经历通过以下途径影响人类成年后的疾病