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

描述（由申请人提供）：核酸的先天免疫识别是警告细胞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与非自我核酸或包含自我核酸，以防止对健康细胞的不正确免疫反应，这通常会导致自身免疫性疾病。本申请旨在了解TREX 1在先天免疫和自身免疫性疾病中的作用。TREX 1是哺乳动物细胞胞质溶胶中最丰富的3 '-5'外切核酸酶。我们的实验室以前已经确定了与系统性狼疮性肾炎（SLE）相关的TREX 1突变。2%的SLE患者携带TREX 1突变，这是确定的单基因SLE的最常见原因。狼疮的高发病率原因是罕见的，因此重要的研究，因为他们有可能提供直接的发病机制的见解。其他TREX 1突变体也已被确定与Aicardi-Goutieres综合征（AGS）和视网膜血管病变和脑白质营养不良（RVCL）相关。Trex 1-/-小鼠发展出与SLE和AGS相似的自身免疫性炎症表型，例如升高的I型干扰素α（IFNa）。发现在逆转录期间从内源性逆转录元件驱动的胞质ssDNA在Trex 1-/-细胞中积累，这可能是IFN应答的触发器。使用逆转录病毒模拟内源性逆转录因子，我发现它刺激与Trex 1-/-细胞中逆转录因子相同的信号通路，从而代表了一个强大的基于细胞的感染系统，用于研究TREX 1在先天免疫中的功能。本申请的总体主题是理解TREX 1如何抑制对源自逆转录因子和逆转录病毒的胞质DNA的先天免疫应答，以及在不存在TREX 1的情况下，先天免疫如何识别通过逆转录产生的DNA（RT DNA）。我的目的1是验证先天免疫因子发现的初步研究，他们的作用，逆转录病毒刺激的干扰素反应。我已经确定了一些先天免疫因子，它们对逆转录病毒的先天免疫反应起积极或消极的作用。验证这些因素为研究潜在途径建立了框架。目标2中的研究将使用系统的多学科方法定义识别RT DNA并激活IFN的信号通路。 人类中的TREX 1突变引起系统性狼疮性肾炎（SLE）、家族性冻疮狼疮（FCL）、Aicardi-Goutieres综合征（AGS）和视网膜血管病变和脑白质营养不良（RVCL）。这些疾病中的许多显示自身免疫炎性表型，例如升高的IFNa。我的研究将揭示潜在的先天免疫信号通路的分子机制。了解TREX 1在先天免疫中的功能将对其遗传相关的自身免疫性疾病产生广泛影响。来自入侵病原体的遗传物质的先天免疫识别通过诱导抗病毒细胞因子应答来警告细胞。我们的细胞已经进化出区分自我与非自我核酸的方法，例如细胞质中的DNA。对自身DNA的错误识别会导致对健康细胞的免疫反应，这通常会导致自身免疫性疾病。TREX 1最近被认为参与诱导干扰素对内源性逆转录酶的应答; TREX 1基因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（包括系统性狼疮性肾炎）中发生突变。这项研究将提高对TREX 1如何在先天免疫的雷达下保持细胞溶质逆转录因子DNA的理解，以及在没有TREX 1的情况下，如何检测到这些DNA。它也可能为治疗自身免疫性疾病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.