Regulation, function, and impact of developmental retrotransposon activation

发育逆转录转座子激活的调节、功能和影响

• 批准号: 10549855
• 负责人: Zhao Zhang
• 金额: $ 32.66万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549855
• 关键词: Address; Adult; Animals; Antiviral Response; Area; Automobile Driving; Biological; Biological Metamorphosis; Biomedical Research; Cells; DNA Damage; DNA Sequence Alteration; Data; Development; Disease; Drosophila genus; Ensure; Epigenetic Process; Event; Future; Genetic; Genetic Transcription; Goals; Grant; Gypsies; Health; Human; Human Genome; Immune; Immune system; Immunity; Infection; Inflammation; Innate Immune System; Invaded; Laboratories; Learning; Length; Letters; Life Cycle Stages; Malignant Neoplasms; Messenger RNA; Modeling; Modification; Molecular; Monitor; Natural Immunity; Neurodegenerative Disorders; Pathologic; Pathology; Physiological; Physiology; Process; Production; RNA Splicing; Regulation; Research; Resolution; Retrotransposon; Role; Scheme; Shapes; Signal Transduction; System; Technology; Testing; Tissues; Viral; Virus; Virus Diseases; antimicrobial peptide; cancer cell; combat; env Gene Products; fly; genetic element; human disease; immunogenicity; improved; innate immune pathways; insight; novel; pathogen; prevent; programs; spatiotemporal; tissue regeneration; tool; transcriptomics; virology

ABSTRACT Retrotransposons are the most abundant genetic elements in almost all animal cells, making up 38% of the human genome. Their activation inherently leads to DNA damage and mutations, and this activity is increasingly appreciated to cause numerous human diseases. Despite their abundance and fundamental impacts on host physiology and pathology, the study of retrotransposons remains an underexplored area of biomedical research. Using new tools and technologies developed by my team, in the long-term, we aim to understand how retrotransposon activity is developmentally regulated, and what are the function and impact of their developmental activation to the hosts under physiological and pathological conditions. Our early progress revealed an unexpected convergence among developmental retrotransposon activation, host immunity, and antiviral response. These results lead to our central hypothesis that developmentally programed retrotransposon activation primes the immune system to grant the hosts a long-term protection against future pathogen infections. Toward this hypothesis, we have discovered that Gypsy retrotransposon selectively becomes active in the newly regenerating tissues during Drosophila metamorphosis. We have also found that Gypsy activation triggers the production of antimicrobial peptides (AMPs), the effectors of innate immunity. Excitingly, we further learned that suppressing Gypsy activation during metamorphosis leads flies to succumb to viral infection at adulthood. Guided by these strong preliminary data, we propose to pursue three Specific Aims to characterize this Gypsy activation mechanism and to uncover how Gypsy signals AMP production and ultimately promotes an antiviral response: (1) Characterize how Gypsy activity is regulated during animal development. (2) Elucidate the molecular mechanisms by which Gypsy activation primes host innate immunity. (3) Define the long-term impact of Gypsy activation on combating pathogens. Collectively, our proposed research will broadly impact the field by identifying new mechanisms that control retrotransposons and characterizing the influence of retrotransposon on host immunity. Given that the activation of retrotransposon likely contributes to inflammation in neurodegenerative disease and increases immunogenicity of cancer cells, our findings will potentially provide new perspectives to harness them for treating related diseases.

抽象的 逆转录转座子是几乎所有动物细胞中最丰富的遗传元件，占全部细胞的38% 人类基因组。它们的激活本质上会导致 DNA 损伤和突变，并且这种活动越来越多 被认为会导致许多人类疾病。尽管它们丰富且对宿主产生根本性影响 生理学和病理学中，逆转录转座子的研究仍然是生物医学研究中尚未探索的领域。 从长远来看，使用我的团队开发的新工具和技术，我们的目标是了解如何 逆转录转座子活性受到发育调控，其功能和影响是什么？ 在生理和病理条件下对宿主的发育激活。 我们的早期进展揭示了发育逆转录转座子激活、宿主之间的意外趋同 免疫力和抗病毒反应。这些结果引出了我们的中心假设：发育程序 逆转录转座子激活可启动免疫系统，为宿主提供长期保护以应对未来 病原体感染。针对这一假设，我们发现吉普赛逆转录转座子选择性地 在果蝇变态过程中，在新再生的组织中变得活跃。我们还发现 吉普赛激活会触发抗菌肽（AMP）的产生，这是先天免疫的效应物。 令人兴奋的是，我们进一步了解到，在变态过程中抑制吉普赛激活会导致果蝇屈服 成年后病毒感染。在这些强有力的初步数据的指导下，我们建议采取三项具体行动 旨在描述 Gypsy 激活机制的特征，并揭示 Gypsy 如何发出 AMP 产生信号和 最终促进抗病毒反应：（1）描述吉普赛人的活动在动物活动期间是如何受到调节的 发展。 (2) 阐明吉普赛激活引发宿主先天免疫的分子机制。 (3) 定义吉普赛激活对对抗病原体的长期影响。 总的来说，我们提出的研究将通过确定控制的新机制来广泛影响该领域 逆转录转座子并表征逆转录转座子对宿主免疫的影响。鉴于激活 逆转录转座子可能会导致神经退行性疾病中的炎症并增加 癌细胞的免疫原性，我们的发现可能会为利用它们进行治疗提供新的视角 相关疾病。