The Elongation Hypothesis of Autism

描述（由申请人提供）：自闭症谱系障碍（ASD）现在在美国每88个儿童中就有1个受到影响（CDC报告，2012）。患有自闭症谱系障碍的个体表现出的症状包括沟通和社会互动方面的缺陷以及重复行为。许多与突触形成和功能相关的基因在ASD患者中发生突变，这表明自闭症是一种突触紊乱。对于患者及其护理人员来说，自闭症谱系障碍是一种使人终生衰弱的疾病，因此寻找诊断、治疗和预防自闭症谱系障碍的新方法仍然是神经科学领域最大的挑战之一。在未发表的研究中，我们有了一个革命性的发现，直接解决了这个挑战。具体来说，我们发现一个单一的分子机制-转录延长-可以直接与大量（>34）突触相关ASD候选基因的表达联系起来。延伸是RNA聚合酶II与许多延伸因子协调，穿过DNA产生基因转录物的过程。这一过程从未在任何脑部疾病的背景下进行过研究。在这里，我们将验证转录伸长缺陷可以减少ASD候选基因的表达和损害突触功能的新假设。ASD患者的临床数据和我们未发表的皮层神经元培养实验有力地支持了这一假设。为了验证这一假设，我们将确定与延伸机制相关的基因在小鼠模型中调节a)许多ASD候选基因的表达，b)突触功能和c) ASD样行为的程度。我们注意到至少有10个与转录延伸相关的基因在ASD患者中发生突变。我们将确定这10个突变在多大程度上损害神经元中已知ASD基因的转录延伸和表达。最后，我们描述了一种新的方法，它将使我们能够识别环境中常见的有害化学物质

DESCRIPTION (provided by applicant): Autism spectrum disorders (ASD) now affect an astounding 1 in every 88 children in America (CDC Report, 2012). Individuals with ASD show symptoms that include deficits in communication and social interactions as well as repetitive behaviors. A number of genes associated with synapse formation and function are mutated in patients with ASD, suggesting autism is a disorder of the synapse. ASD is a debilitating lifelong medical condition for patients and their caregivers, so finding new ways to diagnose, treat and prevent ASD remains one of the biggest challenges in neuroscience. In unpublished studies, we made a revolutionary discovery that directly addresses this challenge. Specifically, we found that a single molecular mechanism-transcription elongation-can be directly linked to expression of a large number (>34) of synapse-associated ASD candidate genes. Elongation is the process where RNA polymerase II, in coordination with numerous elongation factors, traverses DNA to generate a gene transcript. This process has never been studied in the context of any brain disease. Here, we will test the novel hypothesis that deficits in transcription elongation can reduce expression of ASD candidate genes and impair synapse function. This hypothesis is strongly supported by clinical data from ASD patients and by our unpublished experiments with cultured cortical neurons. To test this hypothesis, we will determine the extent to which genes associated with the elongation machinery regulate a) expression of numerous ASD candidate genes, b) synapse function and c) ASD-like behaviors in mouse models. We noticed that at least 10 genes associated with transcription elongation are mutated in patients with ASD. We will determine the extent to which these 10 mutations impair transcription elongation and expression of known ASD genes in neurons. Lastly, we describe a novel approach that will allow us to identify chemicals commonly found in the environment that impair