Understanding the role of TREX1 in the innate immunity and autoimmune diseases

描述(申请人提供)：对核酸的天然免疫识别是提醒细胞注意入侵者的重要防御机制。我们的细胞已经进化出复杂的机制来区分自我和非自我核酸，或者包含自己的核酸，以防止对健康细胞的不正确免疫反应，这往往会导致自身免疫性疾病。本研究旨在了解TREX1在先天免疫和自身免疫性疾病中的作用。TREX1是哺乳动物细胞胞浆中含量最丰富的3‘-5’外切酶。我们的实验室之前已经发现了与系统性红斑狼疮(SLE)相关的TREX1突变。2%的SLE患者存在TREX1突变，这是已确定的单基因SLE最常见的单一原因。狼疮的高外显性原因很少见，因此研究它们很重要，因为它们有可能提供对发病机制的即时洞察。其他TREX1突变也被发现与Aicardi-Goutieres综合征(AGS)、视网膜血管病和脑白质营养不良(RVCL)有关。TREX1-/-小鼠出现类似于SLE和AGS的自身免疫性炎症表型，例如I型干扰素a(IFNA)升高。在逆转录过程中，内源性逆转录元件驱动的胞浆单链DNA在TREX1-/-细胞中积累，这可能是干扰素应答的触发因素。利用逆转录病毒模拟内源性逆转录元件，我发现它在TREX1-/-细胞中刺激与逆转录元件相同的信号通路，从而代表了一个强大的基于细胞的感染系统，用于研究TREX1在先天性免疫中的作用。本应用的总体主题是了解TREX1如何抑制来自逆转录元件和逆转录病毒的胞浆DNA的先天免疫反应，以及在缺乏TREX1的情况下，逆转录(RT DNA)产生的DNA如何被先天免疫识别。我的目标1是验证从初步研究中发现的先天免疫因子在逆转录病毒刺激的干扰素反应中的作用。我已经确定了一些先天免疫因素，它们对逆转录病毒的先天免疫反应起积极或消极的作用。验证这些因素建立了研究潜在途径的框架。AIM 2中的研究将使用系统的多学科方法定义识别RT DNA和激活干扰素的信号通路。 与公共卫生相关的人类TREX1突变会导致系统性红斑狼疮(SLE)、家族性冻疮性狼疮(FCL)、艾卡迪-古蒂埃综合征(AGS)以及视网膜血管病和脑白质营养不良(RVCL)。其中许多疾病表现为自身免疫性炎症表型，如IFNA升高。我的研究将揭开先天免疫信号通路的分子机制。了解TREX1在先天性免疫中的作用将对其遗传相关的自身免疫性疾病产生广泛的影响。对入侵病原体遗传物质的天生免疫识别通过诱导抗病毒细胞因子反应来提醒细胞。我们的细胞已经进化出区分自我和非自我核酸的方法，比如胞浆中的DNA。对自身DNA的错误识别会导致对健康细胞的免疫反应，这往往会导致自身免疫性疾病。最近，TREX1被认为与诱导干扰素对内源性逆转录因子的反应有关；在类似先天性病毒感染的儿童炎性疾病和自身免疫性疾病中，TREX1基因发生突变，包括系统性红斑狼疮。这项研究将加深对TREX1如何将胞浆反转录元件DNA保持在先天免疫雷达下的理解，以及在TREX1缺失的情况下，这些DNA如何被检测到。它还可能为治疗自身免疫的新疗法和药物靶点指明方向。

DESCRIPTION (provided by applicant): Innate immune recognition of nucleic acid is an important defense mechanism to alert the cell of an invader. Our cells have evolved sophisticated mechanism to distinguish self verse non-self nucleic acid or to contain self nucleic acid to prevent incorrect immune response to healthy cells that often lead to autoimmune diseases. This application seeks to understand the role of TREX1 in the innate immunity and autoimmune diseases. TREX1 is the most abundant 3'-5' exonulease in the cytosol of mammalian cells. Our lab has previously identified TREX1 mutations that are associated with systemic lupus erythematosis (SLE). Two percent of SLE patients harbor mutations in TREX1, representing the single most common cause of monogenic SLE identified. High penetrance causes of lupus are rare and therefore important to study because they have the potential to provide immediate insights into pathogenesis. Other TREX1 mutants have also been identified to associate with Aicardi-Goutieres syndrome (AGS) and retinal vasculopathy and cerebral leukodystrophy (RVCL). Trex1-/- mice develop autoimmune inflammatory phenotypes that are similar to SLE and AGS, such as elevated type I interferon a (IFNa). Cytosolic ssDNA drived from endogenous retroelements during reverse transcription were found to accumulate in Trex1-/- cells that may be the trigger for the IFN response. Using retrovirus to mimic endogenous retroelements, I found that it stimulates the same signaling pathway as described for retroelements in Trex1-/- cells, thereby representing a robust cell-based infection system for studying TREX1 function in the innate immunity. The overall theme of this application is to understand how TREX1 suppresses innate immune response to cytosolic DNA derived from retroelements and retroviruses, and in the absent of TREX1, how DNA generated by reverse transcription (RT DNA) is recognized by the innate immunity. My Aim 1 is to validate innate immune factors uncovered from preliminary studies for their roles in retrovirus-stimulated IFN response. I have identified a few innate immune factors that act positively or negatively on the innate immune response to retrovirus. Validating these factors sets up the framework for studying the underlying pathway. Studies in Aim 2 will define the signaling pathway that recognizes RT DNA and activates IFN using a systematic multidisciplinary approach. Public health relevance TREX1 mutations in humans cause systemic lupus erythematosis (SLE), familial chilblain lupus (FCL), Aicardi-Goutieres syndrome (AGS), and retinal vasculopathy and cerebral leukodystrophy (RVCL). Many of these diseases display autoimmune inflammatory phenotypes such as elevated IFNa. My study will unravel the molecular mechanism of the underlying innate immune signaling pathway. Understanding how TREX1 function in the innate immunity will have broad impact on its genetically linked autoimmune diseases. Innate immune recognition of genetic materials from an invading pathogen alerts the cell by inducing antiviral cytokine responses. Our cell has evolved ways to distinguish self vs non-self nucleic acid such as DNA in the cytosol. Incorrect recognition of self DNA causes immune response to healthy cells that often leads to autoimmune diseases. TREX1 has recently been implicated in inducing interferon in response to endogenous retroelements; and TREX1 gene is mutated in inflammatory diseases of childhood that mimic congenital viral infection and in autoimmune disease, including systemic lupus erythematosis. This study will improve understanding of how TREX1 keeps cytosolic retroelement DNA under the radar of innate immunity, and in the absent of TREX1, how these DNA could be detected. It may also point the way to novel therapies and drug targets for treating autoimmunity.