Studying the Mechanism of Neuronal Dysfunction in SCA7

描述(由申请人提供)： 脊髓小脑性共济失调7(SCA7)是一种由CAG扩张引起的神经退行性和精神障碍，这种扩张发生在编码ataxin-7的SCA7基因中。除了小脑症状和视力下降外，SCA7患者还会出现认知功能障碍和行为问题。我们实验室以前的工作导致了Sca7266Q/SQ敲入(KI)和SCA7敲除(KO)小鼠模型的产生。Sca7266Q/Sq鼠复制了婴儿时期SCA7的所有特征，并降低了海马区CA1区的强直后增强(PTP)。SCA7KO小鼠未受影响，行为正常，但表现出PTP增加。有证据表明Sca7266Q/5Q小鼠转录失调，总体假设是ataxin-7导致基因表达改变，导致海马体和小脑表型。为了验证这一假设，将确定突变小鼠突触功能障碍的程度和时间进程，并测量候选基因的表达水平。在一种互补性的无偏见的方法中，表达谱将被执行，并与表型的开始和进展相关。最后，将采取一种实用的方法，在SCA7小鼠身上进行组蛋白脱乙酰酶266Q/5Q(HDAC)抑制剂的试验。这些研究将为在SCA7突触水平上发生的发病机制提供新的见解，并将在评估一类治疗化合物治疗这种和其他聚谷氨酰胺疾病的疗效方面至关重要。

DESCRIPTION (provided by applicant): Spinocerebellar ataxia 7 (SCA7) is a one of a growing group of neurodegenerative and mental disorders caused by a CAG expansion; this expansion occurs in the SCA7 gene, which encodes ataxin-7. In addition to cerebellar signs and decreased visual acuity, SCA7 patients can suffer from cognitive dysfunction and behavioral problems. Previous work in our laboratory resulted in generation of Sca7266Q/SQ knock-in (KI) and Sca7 knock-out (KO) mouse models. Sca7266Q/SQmice replicate all of the features of infantile SCA7 and have decreased post-tetantic potentiation (PTP) in hippocampal area CA1. Sca7 KO mice are unaffected and behaviorally normal, but exhibit increased PTP. Given evidence for transcriptional misregulation in Sca7266Q/5Q mice, the overall hypothesis is that ataxin-7 causes alterations in gene expression that result in the hippocampal and cerebellar phenotypes. To test this hypothesis, the extent and time course of synaptic dysfunction in mutant mice will be determined and the expression levels of candidates will be measured. In a complementary unbiased approach, expression profiling will be carried out and correlated with phenotype onset and progression. Finally, a practical approach will be taken by conducting trials of histone deacetylase;266Q/5Q (HDAC) inhibitors in Sca7 mice. These studies will provide novel insight into mechanisms of pathogenesis that occur at the level of the synapse in SCA7, and will be crucial in evaluating the efficacy of a class of therapeutic compounds in treatment of this and other polyglutamine diseases.