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IMMUNOPATHIC MYOSITIS INDUCED BY PERSISTENT VIRUS

持续病毒引起的免疫病性肌炎

基本信息

批准号：
6532703
负责人：
RONALD P MESSNER
金额：
$ 25.8万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-09-30 至 2004-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6532703
关键词：
Coxsackievirus autoimmune disorder autoimmunity chronic disease /disorder computer assisted sequence analysis disease /disorder etiology genetic strain genome host organism interaction immunopathology inflammation laboratory mouse myositis nucleic acid sequence virus genetics

项目摘要

Prior enterovirus infection has been implicated in pathogenesis of certain human autoimmune diseases including the idiopathic inflammatory myopathies, juvenile-onset diabetes, and cardiomyopathy, as well as noninflammatory diseases like chronic fatigue syndrome. How the elements of enteroviral infection are linked to development of post-viral disease is unclear, but the process is probably driven by factors inherent in viral and host genomes and possibly by interaction of these factors with other environmental stimuli. This proposal is focused on identifying the specific viral gene or genes that are crucial to disease induction in a well-characterized mouse model of chronic inflammatory myopathy (CIM). CIM is induced in susceptible mouse strains by neonatal infection with coxsackievirus B1 (CVB1). A panel of CVB1 variants has been produced that are myopathic (MP) or amyopathic (AMP) with respect to CIM induction and which will be used to identify the viral components that mediate CIM development. First, infectious cDNA clones from both a prototypic MP and an AMP variant will be produced. Pathogenic phenotypes of the cloned viruses will be tested in vivo to confirm that they are equivalent to the parental viruses. The two prototypic viral clones will then be sequenced to identify specific genomic differences and construct a map of putative myopathogenicity-inducing regions. Next, the functional significance of these differences will be tested by creating MP/AMP chimeras from the clones and evaluating CIM induction using a panel of five pathologic indicators. In vivo infection with reciprocal chimeras will confirm which genomic regions are coupled to CIM development. The effect of specific genetic differences will then be verified at the single nucleotide level. Myopathic regions in the remaining variants will be examined to determine if amyopathic changes in the AMP prototype are conserved or if different mutations have occurred which have the same functional effect. This will also reveal whether the dominant disease determinants have been mapped or if additional viral genes are involved. MP3, a unique variant that induces weakness in the absence of inflammation, will be examined more extensively to answer questions regarding the interrelatedness of viral genes that induce weakness and inflammation. This study will identify which determinants of the virus interact with the host to precipitate the development of chronic immunopathic disease. Focused, mechanistic hypotheses can then be developed to explore these interactions in future studies.

先前的肠道病毒感染已经涉及某些人类自身免疫性疾病的发病机制，包括特发性炎性肌病、青少年发病的糖尿病和心肌病，以及非炎性疾病如慢性疲劳综合征。肠道病毒感染的要素如何与病毒后疾病的发展相关联尚不清楚，但该过程可能是由病毒和宿主基因组中固有的因素驱动的，并且可能是由这些因素与其他环境刺激的相互作用驱动的。该建议的重点是确定特定的病毒基因或基因，是至关重要的疾病诱导在一个良好的特征小鼠模型的慢性炎症性肌病（CIM）。新生小鼠感染柯萨奇病毒B1（CVB 1）可诱导CIM。已经产生了一组CVB 1变异体，它们在CIM诱导方面是肌病性（MP）或无肌病性（AMP）的，并且将用于鉴定介导CIM发展的病毒组分。首先，将产生来自原型MP和AMP变体的感染性cDNA克隆。将在体内检测克隆病毒的致病性表型，以确认其与亲本病毒等同。然后对两个原型病毒克隆进行测序，以确定特定的基因组差异，并构建推定的肌病诱导区域的图谱。接下来，将通过从克隆中产生MP/AMP嵌合体并使用一组五个病理指标评估CIM诱导来测试这些差异的功能意义。用相互嵌合体的体内感染将确认哪些基因组区域与CIM发育偶联。然后将在单核苷酸水平上验证特定遗传差异的影响。将检查剩余变体中的肌病区域，以确定AMP原型中的肌病变化是否是保守的，或者是否发生了具有相同功能效应的不同突变。这也将揭示显性疾病决定因素是否已被定位，或者是否涉及其他病毒基因。 MP3是一种在没有炎症的情况下诱导虚弱的独特变体，将被更广泛地研究，以回答有关诱导虚弱和炎症的病毒基因的相互关联性的问题。这项研究将确定病毒的哪些决定因素与宿主相互作用，以促进慢性免疫性疾病的发展。然后，可以开发重点，机制的假设，以探索这些相互作用在未来的研究。