Mechanisms and effects of GABAbR dephosphorylation during ischemic excitotoxicity

描述（由申请人提供）：亨廷顿舞蹈病（HD）是一种神经退行性疾病，其特征是运动、认知和情绪症状的衰弱。它是由亨廷顿蛋白（HTT）基因中显性遗传CAG三重重复扩增引起的，通过突变HTT蛋白功能的毒性获得和对野生型HTT关键功能的干扰，导致HD病理。该研究旨在更好地阐明野生型人类HTT基因的表达是如何受到与自闭症相关的原人特异性长链非编码RNA （lncRNA）的调控，并强调其在大脑中的潜在重要性。初步数据表明，lncRNA在人脑中的表达与HTT mRNA的区域富集模式相似，并且在表达两种人类基因的转基因小鼠中，lncRNA增加了人类HTT的表达。细胞培养试验将研究HTT基因中的内含子转座元件是否必要和充分地赋予lncRNA对其的调节，并确定lncRNA招募的染色质重塑过程以增加HTT转录。人类lncRNA和HTT基因随后将在转基因小鼠中表达，以重建遗传调控系统。这些小鼠的实验将检验lncRNA表达对分子、细胞和行为过程的影响，这些过程在野生型HTT中增强，在HD模型中受损。具体来说，Morris水迷宫中的神经元基因转录、细胞凋亡、囊泡运动、焦虑样行为和认知功能将被检测。阐明这种新颖的、控制野生型HTT表达的人类特异性机制，将提供对HD病理影响的正常功能的更彻底的理解，并可能因此推动改进治疗的发展。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a neurodegenerative disorder marked by debilitating motor, cognitive, and emotional symptoms. It is caused by a dominantly inherited CAG triplet repeat expansion in the Huntingtin (HTT) gene, which gives rise to HD pathology both via toxic gains of function of the mutant HTT protein and interference with the critical functions of wild-type HTT. This proposal seeks to better elucidate how the expression of the wild-type human HTT gene is regulated by a hominid-specific long noncoding RNA (lncRNA) that has been linked to autism, highlighting its potential importance in the brain. Preliminary data indicate that the lncRNA is expressed in the human brain in a similar regional enrichment pattern as HTT mRNA, and that it increases human HTT expression in transgenic mice expressing both human genes. Cell culture assays will investigate whether an intronic transposable element in the HTT gene is necessary and sufficient to confer its regulation by the lncRNA, and to identify the chromatin remodeling processes that are recruited by the lncRNA to increase HTT transcription. The human lncRNA and HTT genes will then be expressed in transgenic mice to reconstitute the genetic regulatory system. Experiments in these mice will examine the effects of lncRNA expression on molecular, cellular, and behavioral processes that are enhanced by wild-type HTT and impaired in HD models. Specifically, neuronal gene transcription, apoptosis, vesicle motility, anxiety-like behaviors, and cognitive function in the Morris water maze will be assayed. Illuminating this novel, hominid-specific mechanism controlling the expression of wild-type HTT will provide a more thorough understanding of the normal functions that HD pathology impinges upon, and may thereby advance the development of improved therapies.