NOVEL BIOMARKERS IN HUNTINGTON'S DISEASE

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 亨廷顿氏病（HD）是一种常染色体显性遗传的进行性神经退行性疾病，其引起不自主运动、行为和精神症状、认知功能障碍，并且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的发病机制与转录失调有关。 先前对HD小鼠模型中基因表达的分析表明，突变亨廷顿蛋白导致纹状体以及骨骼肌中几组基因的下调（2，3），表明突变亨廷顿蛋白可能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含有普遍存在的转录因子Sp1的结合位点，这表明突变亨廷顿蛋白可能干扰许多含有Sp1因子的组织中的基因转录（3，4）。因此，我们假设突变亨廷顿蛋白可能会失调血细胞中的基因表达来自HD主题。 拟议的研究旨在开发一种基于人类血液样本中观察到的差异基因表达模式的HD发作和进展的简单诊断测试。 由于中枢和外周生物过程在HD中被破坏，人类细胞表现出可以诊断该疾病的基因表达模式，并且对HD具有特异性。 因此，我们建议开发一种新的替代标记物，该标记物对基于症状前基因检测已知携带基因突变的个体（即尚未表现出运动体征的个体）的疾病发作预测敏感，并对有症状个体以及HD特异性的疾病进展监测敏感。此外，我们将试图确定是否参与线粒体CREB在人类线粒体基因的表达是类似于在小鼠模型中观察到的HD。 多聚谷氨酰胺介导的基因和蛋白质水平变化可以在CNS外的组织中检测到的证明提高了疾病进展的生物标志物将在皮肤、肌肉、血液或其他外周可及组织中检测到的可能性。 由于目前HD的临床试验终点仍然不令人满意，因此希望生物标志物可以作为临床试验中的替代物，就像降低胆固醇水平用于评估最终减少冠状动脉疾病心脏骤停的药物的疗效一样。

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.