L-type Calcium Channel Regulation of Neuronal Differentiation

L型钙通道对神经元分化的调节

• 批准号: 7909748
• 负责人: GEORGIA PANAGIOTAKOS
• 金额: $ 4.14万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-18 至 2013-06-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7909748
• 关键词: Affect; Animals; Autistic Disorder; Biochemical Pathway; Brain; Calcium Channel; Calcium Signaling; Cell Differentiation process; Cell Proliferation; Cerebral cortex; Child; Development; Disease; Equilibrium; Event; Functional disorder; Gene Expression; Goals; Impairment; In Vitro; Inherited; L-Type Calcium Channels; Laboratories; Maintenance; Mental Retardation; Molecular; Mutation; Nervous system structure; Neurodevelopmental Disorder; Neuronal Differentiation; Neurons; Population; Regulation; Research; Series; Signal Transduction; System; Timothy syndrome; Transgenic Mice; Ventricular; Work; autism spectrum disorder; daughter cell; gain of function mutation; in vivo; insight; mouse model; nerve stem cell; neurodevelopment; neurogenesis; programs; public health relevance; voltage

DESCRIPTION (provided by applicant): Mutations in L-type voltage gated calcium channels (LTCs) are associated with autism and other neurodevelopmental disorders. The goal of this project is to investigate how LTCs regulate neural progenitor cell (NPC) proliferation and differentiation. Neural development involves a series of coordinated events that balance maintenance and proliferation of NPCs with the differentiation of daughter cells to generate the neuronal populations that comprise the mature cerebral cortex. LTCs such as CaV1.2 convert electrical signals into calcium signals that control biochemical pathways and activate programs of gene expression in the developing nervous system. A gain of function mutation in CaV1.2 leads to Timothy Syndrome (TS), a multi- systemic disorder characterized by autism and mental retardation. Our laboratory has generated a transgenic mouse model for TS and I have found that there is a significant increase in proliferation of NPCs in the ventricular zone (VZ) of these animals. Using an in vitro system to study neuronal differentiation, I have also found that over-expression of wildtype CaV1.2 or CaV1.2 containing the TS mutation (TS-CaV1.2) results in a dramatic impairment of neuronal differentiation. Furthermore, blocking endogenous LTCs also reduces NPC differentiation in vitro. The goal of this project is to extend these initial findings by investigating both the regulation of CaV1.2 during development and the mechanisms by which these channels control NPC differentiation in vitro and in vivo. These studies will expand our understanding of how activity regulates brain development and will provide new insights into the underlying pathophysiology of autism and mental retardation. PUBLIC HEALTH RELEVANCE: Autism spectrum disorders affect more than a million children in the US. The research described here focuses on an inherited form of autism called Timothy Syndrome that is caused by a mutation in the voltage-gated calcium channel CaV1.2. This work will explore the mechanisms by which this mutation influences neurogenesis in the developing brain and will provide insights into cellular and molecular mechanisms that may cause autism in Timothy Syndrome, as well as other autism spectrum disorders.

描述（由申请人提供）：L 型电压门控钙通道（LTC）的突变与自闭症和其他神经发育障碍有关。该项目的目标是研究 LTC 如何调节神经祖细胞 (NPC) 增殖和分化。神经发育涉及一系列协调事件，这些事件平衡 NPC 的维持和增殖与子细胞的分化，以产生构成成熟大脑皮层的神经元群。 CaV1.2 等 LTC 将电信号转换为钙信号，控制生化途径并激活发育中的神经系统中的基因表达程序。 CaV1.2 的功能获得性突变会导致蒂莫西综合症 (TS)，这是一种以自闭症和智力迟钝为特征的多系统疾病。我们的实验室已经建立了 TS 转基因小鼠模型，我发现这些动物的心室区 (VZ) 中 NPC 的增殖显着增加。使用体外系统研究神经元分化，我还发现野生型 CaV1.2 或含有 TS 突变的 CaV1.2 (TS-CaV1.2) 的过度表达会导致神经元分化的严重损害。此外，阻断内源性 LTC 还可减少体外 NPC 分化。该项目的目标是通过研究 CaV1.2 在发育过程中的调节以及这些通道在体外和体内控制 NPC 分化的机制来扩展这些初步发现。这些研究将扩大我们对活动如何调节大脑发育的理解，并将为自闭症和智力低下的潜在病理生理学提供新的见解。 公共卫生相关性：自闭症谱系障碍影响着美国超过一百万儿童。这里描述的研究重点是一种称为蒂莫西综合症的遗传性自闭症，它是由电压门控钙通道 CaV1.2 突变引起的。这项工作将探索这种突变影响发育中大脑神经发生的机制，并将提供对可能导致蒂莫西综合症以及其他自闭症谱系障碍的细胞和分子机制的见解。