Protection of early embryogenesis and pluripotent stem cells against genetic parasites through a primitive immune system

通过原始免疫系统保护早期胚胎发生和多能干细胞免受遗传寄生虫的侵害

• 批准号: 10570214
• 负责人: Thomas P. Zwaka
• 金额: $ 34.47万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-23 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570214
• 关键词: Address; Apoptosis; Attention; Cell Communication; Cell Cycle Arrest; Cells; Chromatin; Code; Congenital Abnormality; DNA; DNA Damage; DNA Methylation; Data; Defect; Development; Disease; Double-Stranded RNA; Elements; Embryo; Embryonic Development; Endogenous Retroviruses; Epiblast; Excision; Exogenous Factors; Fossils; Genetic; Genome; Goals; Grant; Growth; Health; Immune; Immune system; Infertility; Investigation; Length; Monitor; Mus; Normal tissue morphology; Nucleic Acids; Outcome; Parasites; Phagocytosis; Physiology; Play; Pluripotent Stem Cells; Police; Pregnancy loss; Process; Proteins; Repetitive Sequence; Research Proposals; Retrotransposon; Risk Factors; Role; Specific qualifier value; Stimulator of Interferon Genes; Stress; System; TP53 gene; Testing; Untranslated RNA; Viral load measurement; Virion; Virus; Work; Zinc Fingers; arms race; blastomere structure; defense response; early pregnancy; early pregnancy loss; embryo cell; embryonic stem cell; experimental study; gene therapy; genetic disorder diagnosis; immunoregulation; novel; peer; replicator; response; sensor; stress granule; tissue culture; transposon/insertion element; viral RNA

PROJECT SUMMARY Relics of mobile DNA make our genomes look like the aftermath of a mob scene. Even worse, some endogenous retrotransposons did not die out, but rather still swarm our cells early in ontogeny. Their actions can seriously damage the genome of the nascent embryo and cause sporadic diseases and infertility. Recently, we discovered a mechanism by which neighboring cells actively remove pluripotent cells that fail to undergo silencing of their endogenous retrotransposons. Our hypothesis is that there is a conditional policing mechanism reminiscent of a primitive immune system. We propose that pluripotent stem cells sense the endogenous retroviral load of their neighboring cells and, if it is higher than their own, act to kill and remove the overloaded cells. Upon completion of the outlined work, we will have (i) probed a previously unexplored sensing mechanism that involves cells “sniffing” one another for endogenous retroviruses and the removal of cells that failed to silence their genetic parasites (Aims 1 and 2) and (ii) tested whether this system is tunable and subject to immune modulation (Aim 3). These outcomes will have a positive impact because they will force us to shift our attention away from solely cell-intrinsic defense strategies towards considering a much more nuanced system in which cells constantly monitor one another for endogenous retrotransposon-related health. Our line of investigation will provide new targets for genetic diagnosis and interventions targeting pregnancy loss and infertility.

项目摘要 移动的DNA的遗迹使我们的基因组看起来像是暴徒现场的余波。更糟糕的是，一些内源性的 反转录转座子并没有消亡，而是在个体发育的早期仍然聚集在我们的细胞中。他们的行为可能会严重 破坏新生胚胎的基因组，引起散发性疾病和不育。最近，我们发现 这是一种机制，通过这种机制，邻近的细胞主动地移除未能进行沉默的多能细胞， 内源性反转录转座子我们的假设是，存在一种有条件的监管机制， 原始免疫系统我们认为，多能干细胞可以感受到它们体内的内源性逆转录病毒负荷。 相邻的细胞，如果它高于它们自己的细胞，则杀死并移除过载的细胞。完成后 在概述的工作中，我们将（i）探索一种以前未探索过的涉及细胞的传感机制 “嗅探”另一个内源性逆转录病毒和去除细胞，未能沉默其遗传 寄生虫（目标1和2）和（ii）测试该系统是否可调并受到免疫调节（目标 3）。这些结果将产生积极的影响，因为它们将迫使我们将注意力从仅仅 细胞内在的防御策略，以考虑一个更微妙的系统，其中细胞不断 相互监测内源性反转录转座子相关的健康状况。我们的调查将提供新的 基因诊断和针对流产和不孕症的干预措施的目标。