The Histone Demethylase SMCX/JARED1C as a Therapeutic Target for Huntington's Dis

描述(申请人提供)：目前还没有针对亨廷顿病(HD)的疾病修正治疗方法，HD是一种高度复杂的神经退行性疾病，由亨廷顿蛋白(Htt)编码基因内的多谷氨酰胺重复扩张引起。HD治疗干预的有效靶点目前仅限于HD基因转录本及其多肽产品。这项建议的重点是探索一种潜在的治疗HD的新靶点，组蛋白去甲基酶SMCX/JARID1C。这项工作的动力来自于对编码BDNF的基因表达的研究，BDNF是大脑皮层表达的中枢神经系统神经元生存所必需的一种关键神经营养因子。脑源性神经营养因子的进行性耗竭和沿皮质纹状体轴突顺行运输至纹状体的脑源性神经营养因子供应减少与HD的神经病理密切相关。然而，BDNF表达水平的降低只是转录失调的一个方面，转录失调是HD病理的最早阶段的特征。其他神经元基因，如多巴胺受体2(DRD2)和前脑啡肽原(PPE)在HD早期的mRNA表达水平可重复性降低，除BDNF外，这些转录本的表达降低也可能与HD的发病机制有关。我们发现在HD小鼠大脑皮质(R6/2)的BDNF启动子上，活跃转录的表观遗传标记H3K4me3减少。此外，我们发现H3K4me3特有的去甲基酶SMCX/JARID1C在R6/2小鼠的大脑皮层中水平增加。因此，我们假设SMCX/JARID1C活性的增加是HD病理学中的一个关键事件，通过降低SMCX/JARID1C水平可以实现对HD的有效治疗干预。这项建议旨在收集数据来检验这些假设，并为SMCX/JARID1C作为HD治疗干预目标的可能验证提供一个框架。我们的具体目标如下：目的1)对R6/2小鼠大脑中H3K4me3标记改变的病理程序中的H3K4me3标记进行系统的全基因组分析。目的2)检测SMCX/JARID1C基因的急性敲除对表达突变型Htt的小鼠原代神经元的影响。目的3)检测慢性降低SMCX/JARID1C基因表达对HD模型小鼠功能的影响。 与公共卫生相关：亨廷顿病(HD)是一种毁灭性的退行性脑部疾病，不可避免地会导致死亡。目前的治疗方法不能改变疾病的进程；因此，存在一个完全没有得到满足的医疗需求。这些研究的结果将提供重要的临床前数据，这些数据将说明在HD系统中靶向改变DNA结构和转录的酶的翻译效用。

DESCRIPTION (provided by applicant): There are at present no disease-modifying treatments for Huntington's disease (HD) a highly complex neurodegenerative disorder caused by a polyglutamine repeat expansion within the gene encoding the Huntingtin (Htt) protein. Validated targets for therapeutic intervention in HD are currently limited to the HD gene transcript and its polypeptide product. The focus of this proposal is to explore a potential novel therapeutic target for HD, the histone demethylase SMCX/JARID1C. The impetus for this work comes from the study of expression of the gene encoding BDNF, a critical neurotrophic factor essential for survival of CNS neurons expressed in the cerebral cortex. The progressive depletion of BDNF and the decreased supply of BDNF to striatum through anterograde transport down corticostriatal axons is strongly implicated in neuropathology in HD. However, reductions in BDNF expression levels are only one aspect of the transcriptional dysregulation which characterizes the earliest phase of HD pathology. Other neuronal genes such as the dopamine receptor 2 (DRD2) and preproenkephalin (PPE) are reproducibly decreased in mRNA expression levels early in HD and the reduced expression of such transcripts other than BDNF may also be implicated in HD pathogenesis. We find that an epigenetic mark of active transcription, H3K4me3, is decreased at the BDNF promoter in cortex of HD mouse brain (R6/2). Furthermore, we find that a demethylase specific for H3K4me3, SMCX/JARID1C, is increased in levels in the cerebral cortex of R6/2 mice. We therefore hypothesize that increases in SMCX/JARID1C activity are a critical event in HD pathology and that effective therapeutic intervention in HD can be achieved through reductions in SMCX/JARID1C levels. This proposal is designed to gather data which test these hypotheses and provide a framework for the possible validation of SMCX/JARID1C as a target for therapeutic intervention in HD. Our specific aims are as follows: Aim 1) To perform a systematic genome wide analysis of the sites at which the H3K4me3 mark is altered in the pathological program modeling HD in the R6/2 mouse brain. Aim 2) Test the impact of acute knockdown of SMCX/JARID1C in mouse-derived primary neurons expressing mutant Htt. Aim 3) Test the impact of chronic reduction of SMCX/JARID1C levels on functional properties of mouse models of HD. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) is a devastating degenerative brain disease that inevitably leads to death. Current treatments do not change the course of the disease; therefore, a completely unmet medical need exists. The results of these studies will provide important preclinical data that will speak to the translational utility of targeting an enzyme that modifies DNA structure and transcription in HD systems.