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A role for endogenous retroelements in Aicardi-Goutieres Syndrome

内源性逆转录因子在 Aicardi-Goutieres 综合征中的作用

基本信息

批准号：
9296176
负责人：
JOHN Lawrence GOODIER
金额：
$ 20.43万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-14 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9296176
关键词：
17 year old ADAR1 Address Affect Algorithmic Analysis Amyotrophic Lateral Sclerosis Antigens Autoantibodies Autoimmune Process Awareness Basal Ganglia Bioinformatics Biological Assay Blood Brain Calcium Cause of Death Cell Line Cells Cerebrospinal Fluid Cessation of life Childhood Complementary DNA Crows DNA DNA Sequencing Facility Data Deposition Disease Disease Progression Electronic Mail Elements Embryonic Development Encephalopathies Endogenous Retroviruses Enzyme-Linked Immunosorbent Assay Fish Proteins Future Gene Proteins Genes Genetic Transcription Genome Genomics Grant High-Throughput Nucleotide Sequencing Human Human Genome Immune response Immune system Immunology Impairment Individual Infection Inflammatory Innate Immune System Insertion Mutation Interferon Type I Interferons Investigation Laboratories Laboratory Study Leukocytes Life Light Link Malignant Neoplasms Mentors Metabolism Molecular Profiling Multiple Sclerosis Mus Mutation Nervous System Trauma Neuraxis Neurons Nucleic Acids Paste substance Pathology Patients Phenotype Postdoctoral Fellow Process Protein Analysis Proteins Protocols documentation Pseudogenes RNA RNA analysis RNA-Directed DNA Polymerase Recruitment Activity Relaxation Research Research Personnel Retroelements Retrotransposition Retrotransposon Retroviridae Reverse Transcription Rheumatism Role Sampling Serum Severities Signal Transduction Skin Somatic Cell Source Systemic Lupus Erythematosus TREX1 gene Teleconferences Testing Tissues Transgenes Variant Work base brain dysfunction brain tissue cell type cohort early childhood early onset experience functional loss human DNA immunocytochemistry in vivo insight interest leukodystrophy mouse model next generation sequencing novel peripheral blood protein expression pseudotoxoplasmosis syndrome public health relevance response skin lesion systemic autoimmune disease transcriptome sequencing transposon/insertion element treatment strategy

项目摘要

DESCRIPTION (provided by applicant): A role for endogenous retroelements in Aicardi-Goutières syndrome Aicardi-Goutières syndrome (AGS) is a severe Mendelian inflammatory disorder that affects particularly the brain and frequently causes death in childhood. The disease is characterized by progressive encephalopathy, psychomotor regression, and lesions of the skin, together with increased levels of Type I interferon in the cerebrospinal fluid and serum, and induction of interferon-stimulated genes detectable in peripheral blood. Causative mutations have been identified in seven genes, TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1 and IFIH1, with variation in the severity of their associated phenotypes. The protein products of these genes are involved in RNA metabolism or signaling, and have also been linked with suppression of infecting retroviruses and/or endogenous retrotransposons. This study is based on the hypothesis that functional loss of an AGS-associated gene alters the normal metabolism of retrotransposon RNA or its reverse-transcribed cDNA, triggering an interferon response and AGS. Retrotransposons are mobile DNA elements that duplicate themselves by a "copy and paste" mechanism using an RNA intermediate. Endogenous retroviruses (HERVs) comprise 8% of the human genome. Although no HERVs capable of replication have been identified, ongoing HERV expression has been implicated in several disease conditions, including multiple sclerosis, amyotrophic lateral sclerosis, and autoimmune rheumatic disease. LINE1 (L1) retrotransposons occupy 17% of human DNA, although it is believed that only about 100 remain competent for retrotransposition in any individual. L1 retrotransposition has also been responsible for the insertion of over a million non-autonomous Alu retrotransposons and thousands of processed pseudogenes. The cell has evolved defenses restricting retrotransposition, which are occasionally relaxed in certain somatic cell types, notably neuronal cells in the human brain. We predict relaxation of retroelement expression in AGS patients. Using RNA analyses, immunocytochemistry, and functional assays for reverse transcriptase activity, we will examine brain tissue, blood, sera, and derived cell lines from AGS patients to ascertain if retroelement RNA or protein expression is elevated in the disease state. We will determine if de novo L1 and Alu insertion numbers are increased in tissues of AGS patients using high-throughput sequencing protocols. The question of whether L1 expression can induce an interferon response will be addressed using a mouse model harboring an inducible L1 transgene. Finally, we will develop ELISA assays to ascertain if sera from AGS patients contain autoantibodies directed against retroelement proteins. This research should shed new light on a devastating childhood disease and suggest future strategies for treatment. Furthermore, new insights into the interaction of the intrinsic immune system of the cell and endogenous retroelements will be gained.

描述（由申请人提供）：内源性逆转录酶在Aicardi-Goutières综合征中的作用Aicardi-Goutières综合征（AGS）是一种严重的孟德尔炎性疾病，特别影响大脑，经常导致儿童死亡。该疾病的特征在于进行性脑病、精神退化和皮肤病变，以及脑脊液和血清中I型干扰素水平升高，外周血中可检测到干扰素刺激基因的诱导。已经在七个基因TREX 1、RNASEH 2A、RNASEH 2B、RNASEH 2C、SAMHD 1、ADAR 1和IFIH 1中鉴定出致病突变，其相关表型的严重程度不同。这些基因的蛋白质产物参与RNA代谢或信号传导，并且还与感染逆转录病毒和/或内源性逆转录转座子的抑制有关。这项研究是基于这样的假设，即AGS相关基因的功能丧失改变了逆转录转座子RNA或其逆转录的cDNA的正常代谢，引发干扰素反应和AGS。反转录转座子是移动的DNA元件，其通过使用RNA中间体的“复制和粘贴”机制复制自身。内源性逆转录病毒（HERV）占人类基因组的8%。虽然没有HERV能够复制已被确定，正在进行的HERV表达已涉及几种疾病的条件，包括多发性硬化症，肌萎缩侧索硬化症，和自身免疫性风湿性疾病。LINE 1（L1）逆转录转座子占据了人类DNA的17%，尽管据信在任何个体中只有大约100个仍然有能力进行逆转录转座。L1反转录转座还负责插入超过一百万个非自主Alu反转录转座子和数千个加工假基因。这种细胞已经进化出限制反转录转座的防御系统，这种防御系统在某些体细胞类型中偶尔会放松，特别是人脑中的神经元细胞。我们预测在AGS患者中逆转录因子表达的松弛。使用RNA分析，免疫细胞化学和逆转录酶活性的功能测定，我们将检查脑组织，血液，血清和衍生的细胞系从AGS患者，以确定是否retroelement RNA或蛋白质表达升高的疾病状态。我们将使用高通量测序方案确定AGS患者组织中从头L1和Alu插入数是否增加。L1的表达是否可以诱导干扰素反应的问题将解决使用小鼠模型窝藏诱导型L1转基因。最后，我们将开发ELISA检测，以确定是否从AGS患者的血清中含有针对retroelement蛋白的自身抗体。这项研究应该为一种毁灭性的儿童疾病提供新的线索，并为未来的治疗策略提供建议。此外，新的见解的内在免疫系统的细胞和内源性逆转录酶的相互作用将获得。