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。

基本信息

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
项目类别：
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

项目摘要

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.

抽象的。不育是一个影响五对夫妇中一名的问题，但在30％的病例中，不育的原因尚不清楚。对可行配子发展的威胁之一是一个被称为内源的转座子的活动逆转录病毒（ERV）。 ERV具有自我复制，有时动员的能力，创造了新的基因组在同一细胞甚至相邻细胞内插入。以前的研究表明，在果蝇在发育卵的卵泡细胞内的ERV激活会导致不育。当前的解释对于ERV触发的无菌性，ERV从卵泡细胞迁移到卵母细胞并插入自己成为新的基因组基因座，破坏了DNA完整性。但是，我们的实验室没有发现新颖的证据将ERV插入到卵母细胞基因组中，表明不育可能是由未表征引起的机理。在这里，我们提出了一种替代转座子触发的无菌性的解释：我们假设 ERV的压迫通过激活异常的免疫反应引起无菌性。我们发现尽管ERV多动症，但关键免疫途径成分的耗竭仍挽救了生育能力。这些数据提供证据表明转座子触发的无菌性可能是由于免疫激活而不是DNA损伤引起的卵母细胞。该提案旨在调查免疫系统如何认识ERV以及是否免疫反应会导致不育。最终，这些发现可能为 ERV触发的无菌性以及我们对ERV如何影响人类健康的理解。