iFGF14 Regulation of Cerebellar Neuron Excitability

iFGF14 对小脑神经元兴奋性的调节

• 批准号: 8835298
• 负责人: Joseph L. Ransdell
• 金额: $ 5.15万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8835298
• 关键词: Acute; Address; Adult; Affect; Animals; Ataxia; Attenuated; Behavior; Behavioral; Binding; Brain; Cells; Cerebellar Ataxia; Cytoplasmic Granules; Defect; Dependence; Disease; Dominant-Negative Mutation; Equilibrium; Fibroblast Growth Factor; Functional disorder; Goals; Human; Impaired cognition; Inherited; Ion Channel; Ions; Knock-out; Laboratories; Link; Measurement; Mediating; Membrane; Molecular; Motor; Mus; Mutation; N-terminal; Neurologic; Neurons; Phenotype; Physiological; Physiology; Population; Property; Proteins; Psyche structure; RNA Splicing; Regulation; Research; Role; Slice; Sodium; Spinal; System; Testing; Variant; Viral Vector; Work; attenuation; base; cell type; density; fibroblast growth factor-14; improved; in vivo; insight; interest; knock-down; knockout animal; member; mouse model; mutant; nervous system disorder; neuronal excitability; novel; protein function; public health relevance; research study; selective expression; voltage

 DESCRIPTION (provided by applicant): Intracellular Fibroblast Growth Factor 14 (iFGF14) is a novel accessory subunit of voltage gated sodium (Nav) channels9-11 that is linked to spinal cerebellar ataxia 27 (SCA27)3, a debilitating disease, associated with progressive ataxia and mental decline. Previous work in cultured neurons and heterologous expression systems demonstrate that iFGF14 binds to the C-termini of Nav channel pore forming (α) subunits and modulates the properties of the fast transient Nav currents underlying action potentials5,13. iFGF14 is expressed as two N-terminal splice variants in multiple cell types throughout the central nervous system2,4,5. Deletion or knock-down of iFGF14 has recently been shown to attenuate excitability in cerebellar granule and Purkinje neurons7-8, though, an understanding of how iFGF14 regulates excitability in these cell types or its effect on behavior is lacking. The goa of the proposed research is to determine the effect and role of each iFGF14 splice variant in regulating intrinsic excitability of cerebellar neurons; and, to define how dysfunction of iFGF14 expression in cerebellar neurons can result in deleterious phenotypes. To do this, I will utilize viral vectors for acute expression, or knock-down, of iFGF14 in distinct classes of mouse cerebellar neurons. I will also utilize a newly generated mouse model with a knockin SCA27 causing human mutation FGF14145S. With these experimental systems, I will investigate effects of iFGF14 on Nav currents and intrinsic excitability in cerebellar Purkinje and granule neurons from intact slices. I will complete parallel experiments to define the effects of iFGF14 on mouse balance and motor coordination. The results of the proposed experiments will move our understanding of iFGF14 function forward and provide new insights into the mechanisms underlying SCA27 pathophysiology.

 描述（由申请人提供）：细胞内成纤维细胞生长因子14（iFGF 14）是电压门控钠（Nav）通道9 -11的一种新型辅助亚基，与脊髓小脑共济失调27（SCA 27）3相关，SCA 27是一种与进行性共济失调和智力下降相关的衰弱性疾病。先前在培养的神经元和异源表达系统中的工作表明，iFGF 14与Nav通道孔形成（α）亚基的C-末端结合，并调节动作电位基础的快速瞬时Nav电流的性质5，13。iFGF 14在整个中枢神经系统的多种细胞类型中表达为两个N-末端剪接变体2，4，5。iFGF 14的缺失或敲低最近已被证明会减弱小脑颗粒和浦肯野神经元的兴奋性7 -8，但是，对iFGF 14如何调节这些细胞类型的兴奋性或其对行为的影响缺乏了解。拟议研究的果阿是确定每种iFGF 14剪接变体在调节小脑神经元内在兴奋性中的作用和作用;并确定小脑神经元中iFGF 14表达功能障碍如何导致有害表型。为此，我将利用病毒载体在不同类型的小鼠小脑神经元中进行iFGF 14的急性表达或敲低。我还将利用一个新产生的小鼠模型与敲入SCA 27导致人类突变FGF 14145 S。通过这些实验系统，我将研究iFGF 14对来自完整切片的小脑浦肯野和颗粒神经元的Nav电流和内在兴奋性的影响。我将完成平行实验，以确定iFGF 14对小鼠平衡和运动协调的影响。这些实验的结果将推动我们对iFGF 14功能的理解，并为SCA 27病理生理学机制提供新的见解。