High Content Screens of Neuronal Development for Autism Research

用于自闭症研究的神经元发育的高内涵屏幕

• 批准号: 7935500
• 负责人: Shelley L Halpain
• 金额: $ 21.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935500
• 关键词: Angelman Syndrome; Animal Model; Autistic Disorder; Basic Science; Behavioral; Biological Assay; Biological Markers; Biological Models; Brain; Brain region; Cells; Characteristics; Child; Clinical Drug Development; Cognitive deficits; Communities; Data; Databases; Dendritic Spines; Development; Diagnosis; Disease; Economic Burden; Etiology; Exhibits; Family; Fibroblasts; Fragile X Syndrome; Future; Heterogeneity; Human; Image; In Vitro; Individual; Investigation; Length; Libraries; Molecular; Morphogenesis; Morphology; Neurites; Neurons; Patients; Pharmacologic Substance; Phenotype; Pilot Projects; Proteins; Quantitative Microscopy; RNA Interference; Rattus; Reagent; Research; Research Personnel; Rett Syndrome; Screening procedure; Shapes; Software Tools; Staining method; Stains; Stereotyped Behavior; Synapses; Syndrome; Technology; Testing; Time; Vertebral column; abstracting; autism spectrum disorder; base; density; improved; in vitro Assay; induced pluripotent stem cell; language processing; neural circuit; neuron development; neuronal circuitry; novel therapeutics; patient population; pre-clinical; research study; social; social reciprocity; synaptogenesis; trait

DESCRIPTION (provided by applicant): Abnormal development of neuronal circuitry is thought to underlie the characteristic behavioral manifestations of autism spectrum disorder (ASD) and related disorders like Rett syndrome. The aberrant size and function of specific brain regions that has been documented in ASD is likely to result from aberrant development of neurons and synapses, features that can be quantified using in vitro approaches. This application proposes to develop an inexpensive, cell-based assay of neuronal morphogenesis and synaptogenesis that will facilitate both basic research and pre-clinical drug development for ASD. The morphology-based assay will be amenable to automated, high-content screening of neurons derived from either animal models or from induced pluripotent stem cells (iPS cells) from human patients with ASD and related disorders. Neurite outgrowth, dendritic branching, spine shape, and synaptic markers will be quantified. Proof of concept experiments will be conducted to evaluate differences in neuronal development in iPS cells (supplied by collaborator) from Rett syndrome patients compared to unaffected individuals. PUBLIC HEALTH RELEVANCE: This pilot project will develop quantitative, microscopy-based assays of neuronal development that can be used to evaluate neurons derived from lines of induced pluripotent stem cells of patients with autism and related disorders. The assay will facilitate a) the assessment of heterogeneity in neuronal development among patient populations and across individuals with autistic syndromes; b) investigation of molecular mechanisms underlying abnormal neuronal development; and c) screening of pharmaceutical compounds that may improve normal neuronal development in autism.

描述（由申请人提供）：神经元回路的异常发育被认为是自闭症谱系障碍（ASD）和相关疾病（如RETT综合征）的特征行为表现的基础。在ASD中记录的特定大脑区域的异常大小和功能可能是由于神经元和突触的异常发展而导致的，这些特征可以使用体外方法来量化。该应用建议开发出廉价的基于细胞的神经元形态发生和突触发生的测定法，该测定法可以促进基础研究和ASD临床前药物发育。基于形态的测定将适合于自动化的，高筛查的神经元，这些神经元来自动物模型或来自患有ASD和相关疾病的人类患者的诱导多能干细胞（IPS细胞）。将量化神经突生长，树突分支，脊柱形状和突触标记。将进行概念验证实验，以评估RETT综合征患者IPS细胞（合作者提供的）与未受影响的个体相比，IPS细胞（合作者提供的）神经元发育的差异。 公共卫生相关性：该试点项目将开发基于微观显微镜的测定方法，用于评估自闭症患者和相关疾病患者的多能干细胞系列的神经元。该测定将促进a）患者人群和自闭症综合症患者之间神经元发展的异质性评估； b）研究神经元发育异常的分子机制； c）筛选可以改善自闭症正常神经元发育的药物化合物。