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

了解 TREX1 在先天免疫和自身免疫性疾病中的作用

• 批准号: 8091088
• 负责人: Nan Yan
• 金额: $ 16.2万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091088
• 关键词: Antibody Activation; Antiviral Agents; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bacteria; Cell Nucleus; Cells; Cerebrum; Chilblains; Child; Childhood; Complex; Cutaneous; Cytosol; DNA; DNA Viruses; Defense Mechanisms; Detection; Development; Disease; Drug Delivery Systems; Embryo; Encephalopathies; Endosomes; Fibroblasts; Generations; Genetic Materials; HIV; HMGB Proteins; Heart; Human; IRF3 gene; Immune; Immune response; Infection; Inflammation; Inflammatory; Interferon Activation; Interferon Type I; Interferons; Invaded; Lead; Life Cycle Stages; Link; Lupus; Mammalian Cell; Mediating; Molecular; Mus; Mutate; Mutation; NF-kappa B; Natural Immunity; Nuclear; Nucleic Acids; Pathogenesis; Pathway interactions; Patients; Penetrance; Phenotype; Phosphodiesterase I; Process; Regulation; Retinal; Retroelements; Retroviridae; Reverse Transcription; Role; SIV; Signal Pathway; Signal Transduction; Simplexvirus; Single-Stranded DNA; Small Interfering RNA; Specificity; Syndrome; System; Systemic Lupus Erythematosus; TLR9 gene; TREX1 gene; Transcript; Vascular Diseases; Virus Diseases; base; cell type; cytokine; human IRF3 protein; improved; insight; interdisciplinary approach; interferon regulatory factor-3; knock-down; leukodystrophy; macrophage; mutant; novel; pathogen; prevent; public health relevance; response; sensor; viral RNA

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.

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身和非自身核酸或含有自身核酸，以防止对健康细胞产生不正确的免疫反应，而这种反应通常会导致自身免疫性疾病。本申请旨在了解 TREX1 在先天免疫和自身免疫性疾病中的作用。 TREX1 是哺乳动物细胞胞质中最丰富的 3'-5' 外切酶。我们的实验室之前已发现与系统性红斑狼疮 (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 的最常见原因。狼疮的高外显率原因很少见，因此研究很重要，因为它们有可能立即深入了解发病机制。其他 TREX1 突变体也已被确定与 Aicardi-Goutieres 综合征 (AGS) 以及视网膜血管病变和脑白质营养不良 (RVCL) 有关。 Trex1-/- 小鼠会出现与 SLE 和 AGS 相似的自身免疫炎症表型，例如 I 型干扰素 a (IFNa) 升高。研究发现，逆转录过程中内源性逆转录元件驱动的胞浆 ssDNA 在 Trex1-/- 细胞中积累，这可能是 IFN 反应的触发因素。使用逆转录病毒模拟内源性逆转录因子，我发现它会刺激与 Trex1-/- 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 TREX1 在先天免疫中的功能。本申请的总体主题是了解 TREX1 如何抑制对来自逆转录元件和逆转录病毒的胞质 DNA 的先天免疫反应，以及在缺乏 TREX1 的情况下，逆转录 (RT DNA) 生成的 DNA 如何被先天免疫识别。我的目标 1 是验证初步研究中发现的先天免疫因子在逆转录病毒刺激的 IFN 反应中的作用。我已经确定了一些对逆转录病毒的先天免疫反应产生积极或消极影响的先天免疫因素。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来定义识别 RT DNA 并激活 IFN 的信号通路。 公共卫生相关性人类TREX1突变会导致系统性红斑狼疮（SLE）、家族性冻疮狼疮（FCL）、Aicardi-Goutieres综合征（AGS）以及视网膜血管病变和脑白质营养不良（RVCL）。许多这些疾病表现出自身免疫炎症表型，例如 IFNa 升高。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 TREX1 在先天免疫中的功能将对与其遗传相关的自身免疫性疾病产生广泛影响。对入侵病原体遗传物质的先天免疫识别通过诱导抗病毒细胞因子反应来警告细胞。我们的细胞已经进化出了区分自身核酸和非自身核酸（例如细胞质中的 DNA）的方法。对自身 DNA 的错误识别会导致对健康细胞的免疫反应，从而常常导致自身免疫性疾病。最近，TREX1 被认为与内源性逆转录因子反应中诱导干扰素有关。 TREX1 基因在模仿先天性病毒感染的儿童炎症性疾病和自身免疫性疾病（包括系统性红斑狼疮）中发生突变。这项研究将加深对 TREX1 如何将胞质逆转录元件 DNA 保持在先天免疫的雷达下，以及在缺乏 TREX1 的情况下如何检测这些 DNA 的理解。它还可能为治疗自身免疫的新疗法和药物靶点指明道路。