Austin 5HT Candidate Gene Discovery with C Elegans

奥斯汀 5HT 候选基因与 C 线虫的发现

基本信息

批准号：
7229936
负责人：
J. Jay Gargus
金额：
$ 15.28万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-01 至 2008-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7229936
关键词：
Animal Model Antidepressive Agents Antipsychotic Agents Autistic Disorder Beauty Behavioral Behavioral Genetics Behavioral Paradigm Biochemical Biochemical Pathway Biological Assay Biological Models Caenorhabditis elegans Calcium/calmodulin-dependent protein kinase Candidate Disease Gene Cells Characteristics Child Chromosome Mapping Class Collaborations DNA Resequencing Databases Defect Development Disease Dissection Double-Stranded RNA Drug Delivery Systems Drug resistance Drug usage Energy Metabolism Etiology Evaluation Exons Facility Construction Funding Category Fluoxetine Food Functional disorder Future Gene Expression Gene Targeting Genes Genetic Genetic Models Genetic Screening Genome Genomics Hereditary Disease Homologous Gene Human Insulin Insulin-Like Growth Factor Receptor Investigation Lead Libraries Life Life Cycle Stages Maps Medicine Metabolic Metabolic Control Metabolism Mitochondria Modeling Molecular Molecular Genetics Molecular Profiling Mutagenesis Mutation Nature Nervous system structure Neurons Numbers Open Reading Frames Organism Pathway interactions Pattern Personal Satisfaction Pharmaceutical Preparations Phenotype Pilot Projects Publishing RNA Interference Receptor Signaling Regulation Regulatory Pathway Reporter Resistance Respiratory Chain Reverse Transcriptase Polymerase Chain Reaction Role Screening Result Screening procedure Seeds Serotonin Serotonin Agents Signal Pathway Signal Transduction Social Interaction Structure System Technology Testing Therapeutic Time Tissues Translational Research Tricyclic Antidepressive Agents Work austin base cohort college communication behavior design developmental disease fatty acid oxidation complex gene discovery gene function genetic analysis in vivo inhibitor/antagonist lipid metabolism man metabolic abnormality assessment mutant neuropsychiatry novel novel diagnostics novel therapeutics promoter prototype receptor response reuptake size sound transcription factor translational study transmission process

项目摘要

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.

描述（由申请人提供）：自闭症谱系障碍是一组行为定义的发育障碍，它们都具有核心缺陷，但是，这些疾病的病理生理学尚未定义。有证据表明，多基因的病因，但是它们所提供的潜在基因和生化途径仍然未知。高血压血症是观察到的最一致的生化特征，但是PI最近发表了明显不同的新生化表型，是线粒体能量代谢代谢（ME）的细微缺陷（ME），最初是在自闭症的特殊子集中发现的。 Gargus和Sze Labs最近在新的Sprague Hall彼此相邻。 SZE实验室一直在模型有机体中对5-ht蛋白（5HT）信号通路进行遗传和行为研究，C秀丽隐杆线虫是一种理想的有机体，非常适合在途径中发现新型基因靶标，并筛选用于改变其的新型治疗方法，因为它具有完全定义的基因组和神经系统，并且只有一个完全定义的基因组和神经系统，并且只有Nine 5ht 5ht 5ht Nine 5ht nine 5ht Nine 5ht nine 5ht nine 5ht nine 5ht nine 5ht。 Sze Lab进行了开创性的研究，证明了5HT在ME中的作用和蠕虫的发育停滞，非常明显的表型“听起来”，就像Gargus Lab在自闭症中讨论的表型一样。 5HT缺陷型蠕虫改变了Dauer停滞，脂肪代谢和DAF2胰岛素/ IGF受体信号转导向DAF16/ FOXO转录因子，这是一种已知可调节ME中基因表达的途径。这两组之间的协同作用，以及在5HT中，ME和发育调控的意外遗传统一在这个强大的动物模型系统中可以通过该信号通路的窗口观察到这一建议。 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用于治疗自闭症（SSRIS，5HT受体阻滞剂和三轮车）的治疗中，以在此途径中定义和分离新型基因3）鉴定和重新鉴定和重新陈述人类同源性候选基因，以对自闭症同学的未来协作研究进行原型测定。