Cockayne syndrome: role of the innate immune response in neurodegeneration

科凯恩综合征：先天免疫反应在神经退行性变中的作用

• 批准号: 8649097
• 负责人: ALAN M WEINER
• 金额: $ 15.3万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649097
• 关键词: Aging; Aicardi' s syndrome; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Agents; Antiviral Response; Autoantibodies; Autoimmune Responses; Biological; Biological Assay; Blood; Brain; C-terminal; Callithrix; Caring; Cells; Childhood; Chimeric Proteins; Clinical; Clinical Trials; Cockayne Syndrome; DNA Repair; Data; Defect; Development; Diagnosis; Diagnostic; Disease; Drug Formulations; ERCC3 gene; ERCC6 gene; Exhibits; Exons; Exploratory/Developmental Grant; Fibroblasts; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; Growth Factor; Health; Hearing; Heterogeneity; Human; Immune response; Immunosuppressive Agents; Infection; Inflammatory; Inflammatory Response; Interferons; International; Intervention; Investigation; Lead; Manuscripts; Messenger RNA; Methodology; Modality; Molecular; Mutation; Myelin; N-terminal; National Institute of General Medical Sciences; Nerve Degeneration; Normal Cell; Null Lymphocytes; Parents; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Primates; Progeria; Protein Array; Proteins; Publishing; Regulatory Pathway; Reporter; Research; Rewards; Role; Serum; Symptoms; Syndrome; Systemic Lupus Erythematosus; Testing; Transcription-Coupled Repair; Translational Research; Transposase; Virus Diseases; Work; base; calcification; chemokine; chromatin remodeling; clinical practice; cohort; cytokine; design; dysmyelination; high reward; high risk; leukodystrophy; mRNA Expression; meetings; novel; novel therapeutics; outcome forecast; protein expression; repository; research study; response; Aging; Aicardi' s syndrome; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Agents; Antiviral Response; Autoantibodies; Autoimmune Responses; Biological; Biological Assay; Blood; Brain; C-terminal; Callithrix; Caring; Cells; Childhood; Chimeric Proteins; Clinical; Clinical Trials; Cockayne Syndrome; DNA Repair; Data; Defect; Development; Diagnosis; Diagnostic; Disease; Drug Formulations; ERCC3 gene; ERCC6 gene; Exhibits; Exons; Exploratory/Developmental Grant; Fibroblasts; Gene Expression; Gene Expression Profile; Genes; Genetic; Goals; Growth Factor; Health; Hearing; Heterogeneity; Human; Immune response; Immunosuppressive Agents; Infection; Inflammatory; Inflammatory Response; Interferons; International; Intervention; Investigation; Lead; Manuscripts; Messenger RNA; Methodology; Modality; Molecular; Mutation; Myelin; N-terminal; National Institute of General Medical Sciences; Nerve Degeneration; Normal Cell; Null Lymphocytes; Parents; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Primates; Progeria; Protein Array; Proteins; Publishing; Regulatory Pathway; Reporter; Research; Rewards; Role; Serum; Symptoms; Syndrome; Systemic Lupus Erythematosus; Testing; Transcription-Coupled Repair; Translational Research; Transposase; Virus Diseases; Work; base; calcification; chemokine; chromatin remodeling; clinical practice; cohort; cytokine; design; dysmyelination; high reward; high risk; leukodystrophy; mRNA Expression; meetings; novel; novel therapeutics; outcome forecast; protein expression; repository; research study; response

DESCRIPTION (provided by applicant): We propose to test an exciting new hypothesis regarding the causes and molecular mechanisms of a devastating childhood neurodevelopmental progeria known as Cockayne syndrome (CS). If our hypothesis is correct, it will open up new therapeutic options for this currently untreatable disease. CS has long been thought to be a disease of DNA repair because all 5 genes that can cause CS (CSA, CSB, XPB, XPD, and XPG) are essential for transcription-coupled nucleotide excision repair (TC-NER). Yet CS patients usually present with myelin defects and brain calcifications resembling those seen in Aicardi- Goutières syndrome (AGS), a childhood neurodevelopmental leukodystrophy caused by constitutive activation of an innate antiviral interferon response in the absence of viral infection. We recently discovered that the CSB gene, which causes over two thirds of all known cases of CS, contains a piggyBac transposon (PGBD3). As a result, the human CSB locus generates not one but two CSB-related proteins: functional CSB, and a CSB-PGBD3 fusion protein joining the N-terminal domain of CSB to a C-terminal PGBD3 transposase domain (Newman et al., 2008). Most surprisingly, we found that expression of the CSB-PGBD3 fusion protein in CSB-null cells induces a powerful interferon-like innate immune response, and that loss of CSB from normal cells also induces an innate antiviral response (Bailey et al., 2012). Our data suggest that the fusion protein may contribute to CS disease, and could provide an entry point for intervention to delay or ameliorate CS symptoms. We propose two complementary aims to determine whether CS patients display a similar interferon, antiviral, inflammatory, or autoimmune response: (Aim 1) Using Affymetrix microarrays, we will compare mRNA expression in peripheral blood mononuclear cells (PBMCs) of CS patients to our published data for CSB-null cells that stably express the CSB-PGBD3 fusion protein. Microarrays will enable us to detect an interferon, antiviral, or inflammatory gene expression signature, even if the genes are downregulated in patients by SOCS1 or related regulatory pathways. (Aim 2) Using Luminex bead-based assays and cell-based reporter assays, we will examine expression of interferons, cytokines, and chemokines at the protein level in CS serum and PBMCs. We will also use Invitrogen ProtoArray v5.0 protein arrays that display >9,000 human proteins to search for CS serum autoantibodies. Our proposal is high risk because the interferon-like response seen in CS cells may be muted in CS patients; however, the rewards could be high because confirmation of an interferon or autoimmune response would justify the use of immunomodulatory or anti-inflammatory biologicals and drugs for treating CS and related conditions.

描述（由适用提供）：我们建议检验一个令人兴奋的新假设，该假设涉及毁灭性的儿童神经发育后代的原因和分子机制，称为Cockayne综合征（CS）。如果我们的假设是正确的，它将为这种目前无法治疗的疾病打开新的治疗选择。长期以来，CS一直被认为是DNA修复的疾病，因为所有5种可能引起CS（CSA，CSB，XPB，XPD和XPG）的基因对于转录偶联的核犹太核犹太人惊喜修复（TC-NER）都是必不可少的。然而，CS患者通常出现髓磷脂缺陷和大脑计算，这些缺陷和大脑的计算重新组合了AICARDI-GOUTIères综合征（AGS），这是一种儿童神经发育性白细胞营养不良，是由病毒感染缺乏先天抗病毒干扰反应的本构激活引起的。我们最近发现，在所有已知病例中，CSB基因都包含Piggybac Transposon（PGBD3）。结果，人CSB基因座不是生成一种而是两种与CSB相关的蛋白质：功能性CSB，而CSB-PGBD3融合蛋白将CSB的N末端结构域与C末端PGBD3转座酶结构域连接起来（Newman等人，2008年）。最令人惊讶的是，我们发现CSB-PGBD3融合蛋白在CSB无效细胞中的表达会诱导强大的干扰素样本的先天免疫响应，而正常细胞中CSB的丧失也诱导了先天的抗病毒药反应（Bailey等人，2012）。我们的数据表明，融合蛋白可能有助于CS疾病，并且可以为延迟或改善CS症状的干预提供一个切入点。我们提出了两个完整的旨在确定CS患者是否显示类似的干扰素，抗病毒，炎症或自身免疫性反应：（ AIM 1）使用Affymetrix微阵列，我们将比较CS患者的外周血单核细胞（PBMC）中的mRNA表达，以表达CSB-Null Cells的CS患者的稳定数据，以表达CSB-null Celts稳定表达CSB-PGSB-PG-PG-PG-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGB-PGD 3。微阵列将使我们能够检测干扰素，抗病毒或炎症基因表达特征，即使SOCS1或相关调节途径在患者中下调了基因。 （AIM 2）使用基于Luminex珠的测定和基于细胞的报告基因测定法，我们将在CS血清和PBMC中检查干扰素，细胞因子和趋化因子的表达。我们还将使用Invitrogen Protoarray V5.0蛋白阵列显示> 9,000人蛋白质来搜索CS血清自身抗体。我们的建议是高风险，因为CS患者可能会在CS细胞中观察到的干扰素样反应。但是，奖励可能很高，因为对干扰素或自身免疫反应的确认将证明使用免疫调节或抗炎的生物制剂和药物用于治疗CS及相关疾病。