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: 10177576
• 负责人: Zhao Zhang
• 金额: $ 32.69万
• 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/10177576
• 关键词: Address; Adult; Animals; Antiviral Agents; 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; Lead; Length; Letters; Life Cycle Stages; Longitudinal Studies; Malignant Neoplasms; Messenger RNA; Modeling; Modification; Molecular; Monitor; Natural Immunity; Neurodegenerative Disorders; Pathologic; Pathology; Physiological; Physiology; Process; Production; Pupa; RNA Splicing; Regulation; Research; Resolution; Retrotransposon; Role; Scheme; Shapes; Signal Transduction; System; Technology; Testing; Tissues; 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 逆转座子是几乎所有动物细胞中最丰富的遗传因素，占38％ 人基因组。它们的激活本质地导致DNA损伤和突变，并且这种活动越来越多 感谢引起许多人类疾病。尽管它们丰富和对主机的根本影响 生理学和病理学，逆转座子的研究仍然是生物医学研究的未经置换领域。 从长远来看，使用我的团队开发的新工具和技术，我们旨在了解如何了解 逆转座子的活动受到发展的调节，其功能和影响是什么 在生理和病理条件下向宿主发育激活。 我们的早期进展表明，发育逆转座子激活的意外收敛，宿主 免疫力和抗病毒反应。这些结果导致了我们的中心假设，该假设是开发编程的 逆转录座子激活Primes免疫系统授予主机对未来的长期保护 病原体感染。朝向这一假设，我们发现吉普赛逆转录子选择性 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 吉普赛激活触发了抗菌肽（AMP）的产生，即先天免疫的效应子。 令人兴奋的是，我们进一步了解到，抑制吉普赛在变形过程中会导致苍蝇屈服 成年后的病毒感染。在这些强大的初步数据的指导下，我们建议追求三个特定的特定 旨在表征这种吉普赛激活机制，并发现吉普赛信号的产生和 最终促进抗病毒反应：（1）表征动物期间如何调节吉普赛活动 发展。 （2）阐明了吉普赛激活素质具有先天免疫力的分子机制。 （3）定义吉普赛激活对打击病原体的长期影响。 总的来说，我们拟议的研究将通过确定控制的新机制来广泛影响该领域 逆转座子并表征逆转录座子对宿主免疫的影响。鉴于激活 逆转录座子的可能导致神经退行性疾病的炎症，并增加 癌细胞的免疫原性，我们的发现将有可能提供新的观点来利用它们治疗 相关疾病。