Austin 5HT Candidate Gene Discovery with C Elegans

描述(由申请人提供)：自闭症谱系障碍是一组行为上定义的发育障碍，都有共同的核心缺陷，然而，这些障碍的病理生理学尚未定义。有证据表明这是一种多基因病因学，但它们所依赖的潜在基因和生化途径仍不清楚。高5-羟色胺血症是观察到的最一致的生化特征，然而PI最近发表了一种明显独特的新的生化表型，即线粒体能量代谢(ME)的微小缺陷，首次在自闭症儿童的特殊亚群中发现。Gargus和Sze实验室最近在新的斯普拉格大厅搬到了毗邻的地方。Sze实验室一直在对模式生物Celegans的5-羟色胺(5-HT)信号通路进行遗传和行为研究，这种生物非常适合在该途径中发现新的基因靶标，并筛选改变它的新疗法，因为它有一个完全确定的基因组和神经系统，只有9个5-HT神经元。Sze实验室进行了开创性的研究，证明了5HT在ME中的作用以及蠕虫的发育停滞，值得注意的是，表型听起来像是Gargus实验室在自闭症中讨论的那些表型。5HT缺陷的蠕虫改变了DADER停滞、脂肪代谢和DAF2胰岛素/IGF受体向DAF16/FOXO转录因子发出的信号，这是一条已知的调节ME相关基因表达的途径。这两个组之间的协同作用，以及令人兴奋的是，在这个强大的动物模型系统中，可以通过这个信号通路的窗口看到5HT、ME和发育调节中不同表型的意外遗传统一，这是这一提议的基础。为了播撒这种新的翻译协作并检验这样一种假设，即在Celegans 5HT信号中的发现将导致引人注目的新的功能候选基因在自闭症的关联研究中进行测试，从而可能导致新的诊断和治疗方法，我们特别提出三个主要目标：1)直接评估缺乏5HT的Celegans的ME和发育停滞2)使用该系统分离对用于自闭症治疗的5-羟色胺能药物(SSRIs、5HT受体阻滞剂和三环类药物)具有耐药性的蠕虫突变体，以定义和分离该通路中的新基因3)对人类同源候选基因的鉴定和重新测序以原型分析用于未来在自闭症队列中的协作研究。

DESCRIPTION (provided by applicant): Autistic spectrum disorders are a group of behavioraily-defined developmental disorders that all share core deficits, however, the pathophysiology of these disorders is undefined. Evidence suggests a multigenic etiology, but the underlying genes and biochemical pathways they subserve remain unknown. Hyperserotonemia is the most consistent biochemical feature observed, however the PI has recently published on an apparently distinct new biochemical phenotype, subtle deficiencies in mitochondrial energy metabolism (ME), first discovered in special subsets of children with autism. The Gargus and Sze labs recently moved adjacent to one another in the new Sprague Hall. The Sze lab had been carrying out genetic and behavioral studies of the serotonin (5HT) signaling pathway in a model organism, C elegans, an organism ideally suited to the discovery of novel gene targets in the pathway, and screening for novel therapeutics that alter it, since it has a completely defined genome and nervous system and only nine 5HT neurons. The Sze lab had carried out pioneering studies demonstrating the role of 5HT in ME and developmental arrest of the worm, remarkably, phenotypes "sounding" like those being discussed in autism by the Gargus lab. 5HT-deficient worms have altered dauer arrest, fat metabolism and altered DAF2 insulin/IGF receptor signaling to the DAF16/ FOXO transcription factor, a pathway known to modulate the expression of genes involved in ME. Synergy between the two groups, and excitement that unexpected genetic unification of disparate phenotypes in 5HT, ME and developmental regulation might be seen through the window of this signaling pathway in this powerful animal model system, underlie this proposal. To seed this new translational collaboration and to test the hypothesis that discoveries in C elegans 5HT signaling will lead to compelling new functional candidate genes to be tested in association studies in autism, potentially leading to novel diagnostics and therapeutics, we specifically propose three primary objectives: 1) Directly assessing ME and developmental arrest in 5HT-deficient C elegans 2) Using this system to isolate worm mutants resistant to the serotonergic drugs used in the treatment of autism (SSRIs, 5HT receptor blockers and tricyclics) to define and isolate novel genes in this pathway 3) Identification and resequencing of human homolog candidate genes to prototype assays for future collaborative studies in autistic cohorts.