Examining the role of immune activation in transposon-triggered sterility.

检查免疫激活在转座子触发的不育中的作用。

• 批准号: 10748032
• 负责人: Kara Michelle Stark
• 金额: $ 4.03万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10748032
• 关键词: Affect; Aging; Apoptosis; Area; Autophagocytosis; Behavior; Binding; Biological Assay; Biological Metamorphosis; Cell Death; Cell Nucleus; Cell Survival; Cells; ChIP-seq; Couples; Cyst; DNA; DNA Damage; Data; Development; Drosophila genus; Egg Preservation; Endogenous Retroviruses; Epigenetic Process; Fertility; Genes; Genome; Genomics; Germ Cells; Health; Human; Human Genome; Hyperactivity; Immune; Immune response; Immune system; Immunosuppression; In Situ Nick-End Labeling; Infertility; Invaded; Learning; LysoTracker; Malignant Neoplasms; Messenger RNA; Modeling; Natural Immunity; Nuclear; Nucleic Acids; Oocytes; Parents; Pathway interactions; Phenotype; Play; Production; Proteins; RNA immunoprecipitation sequencing; Repression; Research; Retrotransposon; Reverse Transcription; Role; Severities; Signal Transduction; Signaling Molecule; Sterility; Structure; Testing; Tissues; Travel; Virus-like particle; defense response; derepression; egg; experimental study; feeding; fly; genetic information; genomic locus; immune activation; insight; migration; novel; offspring; piRNA; success; transcription factor; transmission process; viral detection

ABSTRACT. Infertility is a problem that affects one out of five couples, yet the cause of sterility is unknown in 30% of cases. One threat to viable gamete development is activity of a subset of transposons known as endogenous retroviruses (ERVs). ERVs have the ability to self-replicate and sometimes mobilize, creating new genomic insertions within the same cell or even neighboring cells. Previous studies have demonstrated that, in Drosophila, ERV activation within the follicle cells of developing eggs causes sterility. The current explanation for ERV-triggered sterility postulates that ERVs migrate from the follicle cells into the oocyte and insert themselves into new genomic loci, damaging DNA integrity. However, our lab has found no evidence of novel ERV insertions being made into the oocyte genome, suggesting sterility may arise from uncharacterized mechanism(s). Here, we propose an alternative explanation for transposon-triggered sterility: we hypothesize that ERV derepression induces sterility through activation of an aberrant immune response. We found that depletion of key immune pathway components rescued fertility despite ERV hyperactivity. These data provide evidence that transposon-triggered sterility may be due to immune activation rather than DNA damage within the oocyte. This proposal seeks to investigate how the immune system recognizes ERVs and whether that immune response can cause sterility. Ultimately, these findings may provide an alternative explanation for ERV-triggered sterility as well as advance our understanding of how ERVs impact human health.

摘要。 不孕不育是一个影响五分之一夫妇的问题，但在30%的情况下，不孕不育的原因是未知的。 一个威胁到可行的配子发展是活动的一个子集的转座子称为内源性 逆转录病毒（ERV）。ERV具有自我复制的能力，有时会移动，创造新的基因组。 在同一个细胞甚至相邻细胞中插入。以前的研究表明，在 果蝇中，ERV在发育卵子的滤泡细胞内激活会导致不育。目前的解释 对于ERV触发的不育，假设ERV从卵泡细胞迁移到卵母细胞， 进入新的基因组位点，破坏DNA的完整性。然而，我们的实验室没有发现新的证据， ERV插入到卵母细胞基因组中，这表明不育可能是由未表征的 机制。在这里，我们提出了转座子触发不育的另一种解释：我们假设 ERV去阻遏通过激活异常免疫应答诱导不育。我们发现 尽管ERV过度活跃，但关键免疫途径组分的消耗挽救了生育力。这些数据提供 证据表明，转座子触发的不育可能是由于免疫激活，而不是DNA损伤内 卵母细胞这项提案旨在研究免疫系统如何识别ERV，以及 免疫反应会导致不育最终，这些发现可能会提供另一种解释， ERV引发的不孕症以及推进我们对ERV如何影响人类健康的理解。