Host factors in innate immunity and retroelement control

先天免疫和逆转录因子控制中的宿主因素

• 批准号: 9403751
• 负责人: Charles M Rice
• 金额: $ 25.43万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-26 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9403751
• 关键词: ADAR1; Affect; Antiviral Agents; Antiviral Response; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biology; CRISPR library; CRISPR screen; Cell Line; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Complementary DNA; Custom; Development; ES Cell Line; Elements; Equilibrium; Foundations; Future; Genes; Genetic Transcription; Genome; Germ Cells; Goals; HIV-1; Human Genome; Immune; Immune system; Individual; Innate Immune System; Integration Host Factors; Interferon Type I; Interferons; Knock-out; Lead; Libraries; Malignant Neoplasms; Mediating; Natural Immunity; Nucleic Acids; Paste substance; Pathway interactions; Play; Price; Process; Production; Proteins; RNA Helicase; Reporter; Research; Retroelements; Retrotransposon; Retroviridae; Risk; Role; Signal Transduction; Small RNA; Somatic Cell; Source; Stem cells; Stress; Stress Response Signaling; System; TREX1 gene; Technology; Testing; Vertebrates; Viral Cancer; Virus; Virus Diseases; Work; alertness; base; cancer therapy; cell type; genome-wide; insight; loss of function; novel; personalized approach; pressure; response; tool

Project Summary/Abstract The interferon (IFN)-based innate immune system is the first line of defense against viral infections and cancer. Under constant selective pressure, it has evolved to act quickly and accurately. Yet heightened alertness comes with a price—occasionally self molecules are improperly recognized as foreign and this leads to aberrant IFN production. Thus, the system exists in a delicate balance. From studying autoimmune disorders, we know that endogenous retroelements are a major source of “foreign” nucleic acids and that they trigger aberrant IFN production when improperly controlled. But endogenous retroelements also play important beneficial roles in innate immunity. There's evidence that by maintaining tension in the system, they prime cells for effective antiviral responses. They also act as internal alarms to alert the immune system of danger when transcription is dysregulated in cancer. Several retroelement restriction factors are known and their mechanisms have been studied; however, there are likely more and there is much we don't know about how retroelements are controlled and how they affect innate immunity. The goals of this project are to identify novel host factors involved in retroelement control and to gain mechanistic insight into MOV10's mechanism of action. MOV10 is a potent retroelement restriction factor, and there is evidence that it may inhibit retroelements by a poorly understood small RNA mechanism. If true, identifying host factors required for MOV10 function could provide unique insights into the interplay between the protein-based IFN system used primarily by vertebrates and the more ancient small RNA-based mechanism of antiviral defense used by many other species. The approach that we'll take utilizes state-of-the-art CRISPR screening technology to knockout every gene in the human genome and identify host factors that restrict the replication of an intact LINE-1 retroelement. We will use this same approach to identify host proteins that are required for MOV10 function. The latter will provide useful mechanistic insights that we will explore in more detail using additional retroviral (HIV-1) and retroelement (Alu retrotransposon) tools. We expect that this work will provide new insights that will broaden our understanding of retroelement biology and innate immunity. These results may change the way we think about antiviral mechanisms, autoimmunity, and cancer.

项目总结/摘要 基于干扰素（IFN）的先天免疫系统是抵抗病毒感染和癌症的第一道防线。 在不断的选择压力下，它已经进化到快速准确地行动。但高度的警觉性 这是有代价的--有时自我分子被不恰当地认为是外来的，这导致 干扰素产生异常因此，该系统处于一种微妙的平衡之中。 通过研究自身免疫性疾病，我们知道内源性逆转录酶是自身免疫性疾病的主要来源。 因此，本发明人认识到，当不适当地控制时，它们是“外来”核酸，并且它们触发异常IFN产生。但 内源性逆转录因子在先天免疫中也起重要的有益作用。有证据表明 维持系统中的张力，使细胞产生有效的抗病毒反应。它们也充当内部 当癌症中转录失调时，发出警报以提醒免疫系统危险。几 逆向元件限制因子是已知的，并且已经研究了它们的机制;然而， 还有很多我们不知道的关于逆元素是如何控制的，以及它们是如何影响先天的 免疫力 本项目的目标是确定新的主机因素参与retroelement控制，并获得 对MOV 10的作用机制的机械见解。MOV 10是一种有效的逆向元件限制因子， 有证据表明，它可能通过一种知之甚少的小RNA机制抑制逆转录因子。如果是真的， 确定MOV 10功能所需的宿主因素，可以提供对以下因素之间相互作用的独特见解： 主要由脊椎动物使用的基于蛋白质的干扰素系统和更古老的基于小RNA的干扰素系统。 许多其他物种使用的抗病毒防御机制。 我们将采取的方法利用最先进的CRISPR筛选技术来敲除每个 人类基因组中的LINE-1基因，并鉴定限制完整LINE-1复制的宿主因子 逆元素我们将使用相同的方法来鉴定MOV 10功能所需的宿主蛋白。 后者将提供有用的机制的见解，我们将探讨更详细地使用额外的逆转录病毒 （HIV-1）和retroelement（Alu逆转录转座子）工具。 我们希望这项工作将提供新的见解，将扩大我们对retroelement的理解 生物学和先天免疫这些结果可能会改变我们对抗病毒机制的看法， 自身免疫和癌症