Signaling Pathways in Autism

自闭症的信号通路

• 批准号: 9323602
• 负责人: Jyothi Arikkath
• 金额: $ 7.46万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323602
• 关键词: Affect; Affinity; Affinity Chromatography; Autistic Disorder; Behavioral; Binding; Biochemical; Biology; Cadherins; Cell Adhesion; Cell Nucleus; Cognitive deficits; Complex; Data; Dendrites; Dendritic Spines; Development; Disease; Emotional; Family; Genetic; Genetic Transcription; Healthcare Systems; Hippocampus (Brain); Individual; Intellectual functioning disability; Intervention; Knowledge; Lead; Learning; Molecular; Molecular Abnormality; Morphogenesis; Mus; Mutation; N-terminal; Neurodevelopmental Disorder; Neurons; Nuclear; Pathology; Pharmacology; Phenotype; Protein Region; Proteins; Quality of life; Reagent; Role; Signal Pathway; Societies; Synapses; Synaptosomes; Techniques; Vertebral column; base; delta-catenin; density; insight; interest; mutant; neural circuit; novel; novel therapeutic intervention; social; therapy development

Project Summary: Autism is a debilitating neurodevelopmental disorder associated with social and cognitive deficits. Autism compromises the quality of life of affected individuals and place an enormous financial and emotional burden on families and the healthcare system. Advances that promote novel therapeutic approaches are thus a critical need. Mutations in CTNND2, encoding δ-catenin, have been identified in autism. However, the normal functional roles of δ-catenin and how autism mutations perturb this functional role remain unclear. We have identified critical roles for δ-catenin in regulating dendrites, spines and transcription. Based on our preliminary data, we propose that δ-catenin interacts with specific interactors in different cellular compartments to function in these diverse signaling pathways. Further, we propose that autism mutations perturb these interactions or ability to function in these signaling pathways, thus compromising neural circuit formation and contributing to the phenotype of autism. In this proposal, we propose to take advantage of an affinity purification technique to identify and characterize compartment specific binding partners of δ-catenin from the mouse hippocampus. We expect that these studies will aid in further defining the functional roles of δ−catenin and delineate the signaling pathways that are aberrant in autism associated with mutations in CTNND2. Thus these studies will eventually aid the development of novel therapeutic approaches for this devastating disorder.

项目摘要： 自闭症是一种与社会和认知缺陷有关的令人衰弱的神经发育障碍。自闭症 损害受影响个人的生活质量，并承担巨大的财务和情感负担 关于家庭和医疗保健系统。因此，促进新型治疗方法的进步是关键 需要。 在自闭症中已经确定了CTNND2的突变，编码δ-catenin的突变。但是，正常功能 δ-catenin的作用以及自闭症突变如何扰动该功能的作用尚不清楚。我们已经确定了 δ-catenin在调节树突，刺和转录中的关键作用。根据我们的初步数据，我们 提出δ-catenin与不同细胞隔室中特定相互作用的相互作用以在这些功能起作用 各种信号通路。此外，我们建议自闭症突变会扰动这些相互作用或能力 在这些信号通路中的功能，从而损害了神经回路的形成并有助于 自闭症的表型。 在此提案中，我们建议利用亲和力净化技术来识别和 表征来自小鼠海马的δ-catenin的隔室特异性结合伴侣。我们期望这一点 这些研究将有助于进一步定义δ-catenin的功能作用，并描绘信号通路 与CTNND2突变有关的自闭症异常。这些研究最终将有助于 开发这种毁灭性疾病的新型热方法。