Role of CACNA1C - a shared risk gene in neuropsychiatric disorders

CACNA1C 的作用——神经精神疾病的共同风险基因

• 批准号: 9754880
• 负责人: K Sue Sue O'SHEA
• 金额: $ 38.26万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9754880
• 关键词: Affect; Alleles; Animal Model; Apical; Astrocytes; Behavior; Biological Assay; Biological Models; Bipolar Disorder; Brain; Calcium; Calcium Channel; Calcium Signaling; Cell Line; Cells; Cellular Assay; Characteristics; Collaborations; Complement; DISC1 gene; Data; Data Analyses; Dendrites; Development; Disease; Disease model; Electrophysiology (science); Future; Gene Expression; Gene Expression Regulation; Genes; Genetic Polymorphism; Glutamates; Goals; Growth Cones; Human; Human Activities; Individual; Industrialization; Investigation; Laboratories; Lithium; Major Depressive Disorder; Masks; Measures; Mental disorders; Messenger RNA; Mitochondria; Modeling; Mood Disorders; Morphology; Nervous system structure; Neurites; Neuroglia; Neuronal Differentiation; Neuronal Dysfunction; Neurons; Outcomes Research; Pathway Analysis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Predisposition; Protein Isoforms; Protocols documentation; Publishing; Reproducibility; Research; Risk Factors; Role; Schizophrenia; Signal Transduction; Synapses; Synaptic plasticity; Testing; Tissue Viability; Tissues; Training; Transcriptional Regulation; Validation; Variant; Work; animal data; autism spectrum disorder; base; cell type; cohort; density; disease phenotype; genetic association; gray matter; high throughput analysis; induced pluripotent stem cell; inhibitor/antagonist; miniaturize; mutant; neurogenesis; neuronal circuitry; neuronal excitability; neuropsychiatric disorder; neurotransmitter release; novel; overexpression; predictive test; prognostic assays; relating to nervous system; response; risk sharing; risk variant; scale up; screening; stem cell differentiation; theories; transcriptome; voltage; whole genome

Project 2: Role of CACNA1C – a shared risk factor in neuropsychiatric disorders ABSTRACT A major challenge in understanding human neuropsychiatric disorders has been the lack of viable tissues to analyze. Patient-derived induced pluripotent stem cells (iPSC) now offer the opportunity to examine the full complement of neural tissues and the prospect of identifying underlying disease mechanisms. Despite their promise, “brain in a dish” models can be heterogeneous, masking similarities and subtle differences in disease-related phenotypes. Systematic development and validation of cell-based assays relevant to neuropsychiatric disease are therefore critically required. We are examining the effects of increased CACNA1C expression associated with the AA allele of rs1006737 -- the strongest and most replicated association with bipolar disorder (BP), and also implicated in schizophrenia (SZ) -- in neuronal differentiation and function.This work builds on published investigations in which we have demonstrated a role for CACNA1C in neurogenesis in animal models, and identified alterations in CACNA1C expression, calcium signaling, and neurotransmitter release in neurons differentiated from BP patients compared with those from healthy controls (C). Remarkably, lithium pre-treatment significantly reduced calcium transients and wave amplitude in BP neurons to control levels, providing a tractable model system to identify prognostic tests and examine the response of iPSC- derived neurons to pathway perturbagens and signaling networks suggested to be involved in BP. The overarching goal of the research is to identify predictive tests that distinguish common and divergent disease phenotypes and mechanisms in bipolar disorder and schizophrenia. The scientific hypothesis for this project is that dysregulation of calcium signaling produces subtle but widespread alterations in differentiation, plasticity and activity throughout the nervous system that influence susceptibility to bipolar disorder. Using neurons derived from carriers of the AA allele of rs1006737 and cells from control (GG allele) individuals, we will pursue three Specific Aims. Aim 1 will characterize the differentiation and behaviors of glutamatergic cortical neurons, including neurite outgrowth, synaptic and dendritic behavior, and mitochondrial status. Aim 2 will examine neuronal and network activity. Aim 3 will examine the differentiation of astrocytes and GABAergic neurons, and the effects of normalizing CACNA1C expression on neural differentiation in isogenic cell lines. These studies will directly test a long-standing theory regarding the role of altered calcium signaling in mood disorders and will produce a set of validated protocols comparing DISC1 mutant and BP iPSC, with high throughput analyses to identify novel mechanisms and signaling relevant to neuropsychiatric disease.

项目2：CACNA1C的作用 - 神经精神疾病中的共同风险因素 抽象的 理解人类神经精神疾病的主要挑战是缺乏可行的时机 分析。现在，患者来源的诱导多能干细胞（IPSC）现在提供了检查完整的机会 神经组织的补充和鉴定潜在疾病机制的前景。尽管他们 承诺，“盘中的大脑”模型可能是异质的，掩盖了相似性和微妙的差异 与疾病有关的表型。与基于细胞的测定的系统开发和验证与 因此，至关重要的是神经精神病。我们正在研究增加Cacna1c的影响 与RS1006737的AA等位基因相关的表达式 - 与 双相情感障碍（BP），也与精神分裂症（SZ）有关 - 神经元分化和功能。 作品建立在已发表的研究的基础上，我们证明了CACNA1C在神经发生中的作用 在动物模型中，并确定了CACNA1C表达，钙信号传导和神经递质的改变 与健康对照组相比，与BP患者不同的神经元（C）释放。值得注意的是 锂预处理显着降低了BP神经元中的钙瞬变和波浪放大器以对照 等级，提供一个可易处理的模型系统来识别预后测试并检查IPSC-的响应 派生的神经元到途中扰动途径和信号网络，建议与BP有关。这 该研究的总体目标是确定区分常见和不同的预测测试 躁郁症和精神分裂症的疾病表型和机制。科学假设 对于这个项目，钙信号传导的失调会产生细微但宽度的改变 整个神经系统的分化，可塑性和活动都会影响对 躁郁症。使用源自RS1006737 AA等位基因的载体的神经元和对照的细胞 （GG等位基因）个人，我们将追求三个具体目标。 AIM 1将表征差异化和 谷氨酸能皮质神经元的行为，包括神经元的生长，突触和树突状行为，以及 线粒体状态。 AIM 2将检查神经元和网络活动。 AIM 3将检查差异化 星形胶质细胞和GABA能神经元，以及使CACNA1C表达对神经元的影响 等生细胞系的分化。这些研究将直接检验有关长期存在的理论 情绪障碍中的钙信号改变了，将产生一组经过验证的协议，以比较Disc1 突变体和BP IPSC，具有较高的吞吐量分析，以识别与 神经精神病。