Autism 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学定义的发育障碍，它们都具有核心缺陷，然而，这些障碍的病理生理学尚不明确。 有证据表明是一种多基因病因，但它们所依赖的潜在基因和生化途径仍然未知。 高胆固醇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不同的新生化表型，即线粒体能量代谢（ME）的微妙缺陷，首次发现于自闭症儿童的特殊亚群。 Gargus和Sze实验室最近搬到了新的Sprague Hall。 Sze实验室一直在对模式生物C elegans中的5-羟色胺（5 HT）信号通路进行遗传和行为研究，C elegans是一种非常适合发现该通路中新基因靶点的生物，并筛选改变它的新疗法，因为它具有完全定义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5 HT在ME和蠕虫发育停滞中的作用，值得注意的是，表型“听起来”像Gargus实验室在自闭症中讨论的表型。 5 HT缺陷蠕虫已经改变了dauer停滞、脂肪代谢和改变了DAF 2胰岛素/IGF受体信号传导至DAF 16/ FOXO转录因子，这是已知调节参与ME的基因表达的途径。两组之间的协同作用，以及5 HT中不同表型的意外遗传统一的兴奋，ME和发育调节可能是通过这个强大的动物模型系统中的这个信号通路的窗口看到的，这一建议的基础。 为了播种这种新的翻译合作，并测试这一假设，即在线虫5 HT信号传导中的发现将导致在自闭症的关联研究中测试引人注目的新功能候选基因，可能导致新的诊断和治疗，我们特别提出了三个主要目标：1）直接评估5 HT缺陷型秀丽线虫的ME和发育停滞2）使用该系统分离对用于治疗自闭症的多巴胺能药物具有抗性的蠕虫突变体（SSRI、5 HT受体阻断剂和三环类药物）来定义和分离该途径中的新基因。3）人类同源候选基因的鉴定和重测序，以用于自闭症群体中未来合作研究的原型测定。

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.