Molecular causes of cognitive and autistic disabilities

认知障碍和自闭症障碍的分子原因

• 批准号: 9026843
• 负责人: Michele H. Jacob
• 金额: $ 52.1万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-05 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9026843
• 关键词: Adenomatous Polyposis Coli Protein; Adhesions; Affect; Age; Autistic Disorder; Behavior; Behavioral; Biochemical; Biological Process; Biology; Brain; Brain region; CTNNB1 gene; Cadherins; Child; Cognitive; Cognitive deficits; Collaborations; Complex; Corpus striatum structure; Data; Development; Diagnosis; Disease; Electroencephalography; Electrophysiology (science); Exhibits; Family; Felis catus; Functional disorder; Future; Gene Expression; Gene Mutation; General Population; Genes; Genetic; Genetic Screening; Glutamates; Grant; Hippocampus (Brain); Human; Image; Impaired cognition; Individual; Inherited; Intellectual functioning disability; Knockout Mice; Lead; Link; Mediating; Modeling; Molecular; Molecular Target; Mus; Mutation; Neurodevelopmental Disorder; Neurons; Pathway Analysis; Pathway interactions; Performance; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Prefrontal Cortex; Regulation; Scaffolding Protein; Seizures; Severities; Short-Term Memory; Signal Transduction; Slice; Synapses; Tankyrase; Techniques; Testing; Therapeutic; autism spectrum disorder; beta catenin; brain dysfunction; cognitive change; density; design; disability; disorder risk; effective intervention; gain of function; improved; in vivo; inhibitor/antagonist; insight; interdisciplinary approach; loss of function; loss of function mutation; mouse model; mutant mouse model; neural circuit; novel; overexpression; proband; public health relevance; research study; risk variant; synaptic function; targeted treatment

 DESCRIPTION (provided by applicant): Intellectual disabilities (ID) and autism spectrum disorders (ASD) are highly prevalent. Seizures occur in 10- 30% of individuals with ASD, leading to lifelong disabilities. Treatments are largely lacking because these disorders are molecularly ill-defined. Large-scale genetic screens of families with ASD and ID have identified hundreds of risk genes. Compelling evidence suggests that the risk genes converge on a few key biological processes in neurons. Our grant focuses on two- the β-catenin (β-cat)/ canonical Wnt pathway and synaptic function. β-cat has dual functions in cadherin synaptic adhesion complexes and canonical Wnt signal transduction. Both pathways modulate synapse density and plasticity, as well as the formation and function of circuit networks in the brain. We propose that an optimal range of β-cat levels and its associated pathways is essential; levels too high or low lead to deregulation and brain dysfunction. As support for this hypothesis, several human ID, ASD, and seizure linked genes are predicted to cause either loss- or gain-of-function of the β-cat/ canonical Wnt pathway, highlighting the importance of elucidating the changes caused by aberrant β-cat levels in the brain. Further, our recent studies show that targeted deletion in mouse neurons of adenomatous polyposis coli protein (APC), a major negative regulator of β-cat levels in the canonical Wnt pathway, leads to cognitive and autistic-like disabilities and seizures. Synapse number, maturation and function are altered. Molecular alterations include excessive β-cat and associated changes in Wnt target gene expression and cadherin synaptic adhesion complexes. We propose direct tests of the effects of aberrant β-cat levels in the brain. Aim 1 studies will use our new mouse line with β-cat conditional overexpression in neurons to model gain-of-function. Aim 2 studies will use our new mouse line with conditional deletion of β-cat to model loss-of- function. We will define the cognitive and behavioral phenotypes, their severity, and the molecular and functional changes caused by high versus low β-cat. Aim3 studies will identify drug treatments that correct excessive β-cat levels and test for amelioratio of cognitive deficits, autism-like behaviors and seizures in APC conditional knockout mice. We will also test for rectification of the molecular and functional alterations. Preliminary data provde strong support for our planned studies. All 3 Aims will use the same multidisciplinary approaches to define the behavioral, molecular and functional changes induced by aberrant β-cat levels. This project will utilize the complementary expertise of the Jacob lab in synaptic biology and new genetic mouse models of cognitive and autism-like disabilities, with co-morbid seizures, and the Dulla lab in electrophysiological and network analysis. Our studies will elucidate how alterations in β-cat contribute to the pathophysiology of ID, ASD and seizures on a molecular, synaptic, and circuit level. Our findings will also provide critical insights into the therapeutic potential of targeting β-cat and its associated pathways and thereby inform the design of future therapeutic strategies for these neurodevelopmental disorders.

 描述（由申请人提供）：智力障碍 (ID) 和自闭症谱系障碍 (ASD) 在 10-30% 的 ASD 患者中非常普遍，导致终身残疾，因为这些疾病是分子疾病。 -定义。对患有自闭症谱系障碍和智力障碍的家庭进行的大规模遗传筛查已经发现了数百个风险基因，表明这些风险基因集中在神经元的几个关键生物过程上。 β-连环蛋白 (β-cat)/经典 Wnt 通路和突触功能在钙粘蛋白突触粘附复合物和经典 Wnt 信号转导中具有双重功能。我们认为 β-cat 水平及其相关通路的最佳范围至关重要；或者水平过高； 作为这一假设的支持，一些人类 ID、ASD 和癫痫相关基因预计会导致 β-cat/ 经典 Wnt 通路功能丧失或获得，这凸显了其重要性。此外，我们最近的研究表明，小鼠神经元中腺瘤性息肉病大肠杆菌蛋白 (APC) 的靶向缺失是大脑中 β-cat 水平的主要负调节因子。典型的 Wnt 通路会导致认知和自闭症样障碍以及突触数量、成熟和功能的改变，包括过度的 β-cat 以及 Wnt 靶基因表达和钙粘蛋白突触粘附复合物的相关变化。 Aim 1 研究将使用我们的新小鼠品系在神经元中条件性过度表达 β-cat 来模拟功能获得。研究将使用我们有条件删除 β-cat 的新小鼠品系来模拟功能丧失，我们将定义高 Aim3 与低 β-cat 引起的认知和行为表型、其严重程度以及分子和功能变化。研究将确定纠正β-cat水平过高的药物治疗，并测试APC条件性基因敲除小鼠认知缺陷、自闭症样行为和癫痫发作的改善情况，我们还将测试分子和功能改变的纠正。为我们计划的研究提供强有力的支持。所有 3 个目标将使用相同的多学科方法来定义异常 β-cat 水平引起的行为、分子和功能变化。该项目将利用 Jacob 实验室在突触生物学和新领域的互补专业知识。认知和自闭症样残疾的小鼠模型，以及共病癫痫发作，以及杜拉实验室的电生理学和网络分析，我们的研究将阐明 β-cat 的改变如何影响遗传 ID 的病理生理学，我们的研究结果也将为分子、突触和回路水平的自闭症谱系障碍和癫痫发作提供重要的见解。 靶向β-cat及其相关途径的治疗潜力，从而为这些神经发育障碍的未来治疗策略的设计提供信息。