NOVEL BIOMARKERS IN HUNTINGTON'S DISEASE

亨廷顿病的新型生物标志物

• 批准号: 7607049
• 负责人: HERMINIA Diana ROSAS
• 金额: $ 0.03万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7607049
• 关键词: Behavioral; Binding Sites; Biological Markers; Biological Process; Blood; Blood Cells; Blood specimen; CREB1 gene; Cells; Cessation of life; Cholesterol; Chromosomes, Human, Pair 4; Clinical Trials; Code; Computer Retrieval of Information on Scientific Projects Database; Coronary Arteriosclerosis; Corpus striatum structure; Diagnostic; Diagnostic tests; Disease; Disease Progression; Down-Regulation; End Point; Exhibits; Funding; Gene Expression; Gene Mutation; Gene Proteins; Genes; Genetic Transcription; Genetic screening method; Grant; Heart Arrest; Human; Huntington Disease; Impaired cognition; Individual; Inherited; Institution; Involuntary Movements; Mediating; Mitochondria; Monitor; Motor; Muscle; Neurodegenerative Disorders; Onset of illness; Pathogenesis; Pattern; Peripheral; Research; Research Personnel; Resources; Skeletal Muscle; Skin; Source; Sp1 Transcription Factor; Surrogate Markers; Symptoms; Tissue-Specific Gene Expression; Tissues; Trinucleotide Repeats; United States National Institutes of Health; Work; base; drug efficacy; human Huntingtin protein; mouse model; mutant; novel; polyglutamine; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Huntington's disease (HD) is an autosomal dominantly inherited progressive neurodegenerative disease that causes involuntary movements, behavioral and psychiatric symptoms, cognitive dysfunction and which inexorably leads to death (1). It is caused by the expansion of a triplet repeat on chromosome 4 at the locus of a gene that codes for the 'huntingtin' protein. More recent work has implicated transcriptional deregulation in the pathogenesis of HD. Previous analyses of gene expression in mouse models of HD indicated that mutant huntingtin causes down regulation of several groups of genes in striatum, as well as in skeletal muscle (2,3), suggesting that mutant huntingtin may interfere with transcriptional mechanisms common to many genes. We have found that the known regulatory sequences of these genes contain binding sites for the ubiquitous transcription factor Sp1, suggesting that mutant huntingtin may interfere with gene transcription in many tissues containing Sp1 factor (3,4). Therefore, we hypothesize that mutant huntingtin may deregulate gene expression in blood cells derived from HD subjects. The proposed research study aims to develop a simple diagnostic test for HD onset and progression that is based on the differential gene expression pattern seen in human blood samples. As a result of both central and peripheral biological processes being disrupted in HD, human cells exhibit a gene expression pattern that may be diagnostic for the disease and will be specific for HD. Hence, we are proposing to develop a novel surrogate marker that is both sensitive to predict disease onset in individuals known to carry the genetic mutation on the basis of presymptomatic genetic testing (i.e. individuals who do not yet manifest motor signs) and to monitor disease progression in symptomatic individuals as well as specific to HD. In addition, we will attempt to determine if the involvement of mitochondrial CREB in human mitochondrial gene expression is similar to that observed in mice models of HD. The demonstration that polyglutamine-mediated gene and protein level changes can be detected in tissue outside the CNS raises the possibility that biomarkers of disease progression will be detectable in skin, muscle, blood or other peripherally accessible tissue. Because current clinical trial endpoints for HD remain unsatisfactory, it is hoped that biomarkers can serve as surrogates in clinical trials, much like reduction of cholesterol levels are used to assess the efficacy of drugs that ultimately reduce cardiac arrest from coronary artery disease.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 亨廷顿病 (HD) 是一种常染色体显性遗传的进行性神经退行性疾病，会导致不自主运动、行为和精神症状、认知功能障碍，并不可避免地导致死亡 (1)。 它是由 4 号染色体上编码“亨廷顿蛋白”的基因位点上的三联体重复扩增引起的。 最近的研究表明 HD 的发病机制中存在转录失调。 先前对 HD 小鼠模型中基因表达的分析表明，突变型亨廷顿蛋白会导致纹状体以及骨骼肌中的几组基因下调 (2,3)，这表明突变型亨廷顿蛋白可能会干扰许多基因共有的转录机制。 我们发现这些基因的已知调控序列包含普遍存在的转录因子 Sp1 的结合位点，表明突变型亨廷顿蛋白可能会干扰许多含有 Sp1 因子的组织中的基因转录 (3,4)。因此，我们假设突变型亨廷顿蛋白可能会解除亨廷顿舞蹈症受试者血细胞中基因表达的调节。 拟议的研究旨在开发一种基于人类血液样本中差异基因表达模式的 HD 发病和进展的简单诊断测试。 由于 HD 中枢和外周生物过程都被破坏，人类细胞表现出一种基因表达模式，可以诊断该疾病，并且是 HD 特异性的。 因此，我们建议开发一种新型替代标记，该标记既可以敏感地预测基于症状前基因检测的已知携带基因突变的个体（即尚未表现出运动体征的个体）的疾病发作，又可以监测有症状个体的疾病进展以及 HD 特异性。此外，我们将尝试确定线粒体 CREB ​​在人类线粒体基因表达中的参与是否与 HD 小鼠模型中观察到的相似。 可以在中枢神经系统以外的组织中检测到多聚谷氨酰胺介导的基因和蛋白质水平变化的证明提出了在皮肤、肌肉、血液或其他外周可及的组织中检测到疾病进展的生物标志物的可能性。 由于目前 HD 的临床试验终点仍不令人满意，因此希望生物标志物可以作为临床试验中的替代品，就像降低胆固醇水平用于评估最终减少冠状动脉疾病导致的心脏骤停的药物疗效一样。