Neurotrophic Factor & Neuronal Primary Responses Genes

神经营养因子

• 批准号: 6779073
• 负责人: Harvey R. Herschman
• 金额: $ 34.31万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-06 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6779073
• 关键词: PC12 cells; antisense nucleic acid; cAMP response element binding protein; cell differentiation; electrophysiology; exocytosis; ganglion cell; gene expression; gene induction /repression; gene targeting; genetically modified animals; hippocampus; laboratory mouse; mitogen activated protein kinase; neural plasticity; neurobiology; neurons; neurotrophic factors; oligonucleotides; protein structure function; regulatory gene; synaptic vesicles; synaptotagmin; transcription factor; urokinase

DESCRIPTION (From the Applicant's Abstract): We have two goals in our neurobiological studies. Our first goal has been to identify, in neurons, depolarization-induced immediate-early genes (IEGs) that play a role in synaptic plasticity and to characterize the biochemical mechanisms by which these IEGs mediate synaptic function. Our second goal has been to identify, in neuronal precursors, IEGs induced preferentially by Nerve Growth Factor (NGF) versus other stimulating ligands and to characterize the biochemical mechanisms by which these NGF-induced IEGs mediate NGF-driven neuronal differentiation. We identified synaptotagmin IV (Syt IV) as an IEG induced by depolarization in the hippocampus, prepared anti-Syt IV antibodies and showed that Syt IV is a labile protein incorporated into synaptic vesicles after induced synthesis, where it can form oligomers with Syt I. We created a Syt IV knock-out mouse, and demonstrated that Syt IV (-/-) mice are deficient in acquiring two hippocampal-dependent learning tasks, but not in acquiring two amygdala-associated learning tasks. We subsequently identified four protein kinases (KID-l, PIM-1, SIK, MAPKAP-2) and two transcription factors (nurr1, rTLE3) induced by depolarization. These genes are additional candidate IEGs whose products may mediate synaptic plasticity. We also identified six messages preferentially induced by NGF (versus Epidermal Growth Factor) in the PC12 cell model system of neuronal differentiation. We demonstrated that one of these IEGs, the urokinase plasminogen activator receptor (UPAR), is required for NGF-driven PC12 cell morphological differentiation and secondary response gene expression, using UPAR antisense oligonucleotides and anti-UPAR antibody. We will determine the biochemical basis for Syt IV modulation of synaptic function and collaborate on studies of electrophysiological correlates of the Syt IV (-/-) behavioral deficits. We will determine if Syt IV and our depolarization-induced IEGs are induced via the CREB pathway, and whether they modulate depolarization-induced, calcium-dependent exocytosis. For those IEGs that appear to be good candidates for modulators of synaptic function, we will prepare knock-out mice and analyze their behavioral characteristics. To determine the role of UPAR in NGF-driven neuronal maturation, we will examine development of sympathetic and sensory ganglia in UPAR null mice. We will also use cultured peripheral ganglion cells from BAX/NGF null mice to characterize the role of UPAR in NGF-driven differentiation. Finally, we will determine mechanisms by which (i) NGF induces UPAR and (ii) UPAR modulates NGF-driven neuron differentiation.

描述（摘自申请人摘要）：我们有两个目标

项目成果

Characterization of the rat urokinase plasminogen activator receptor promoter in PC12 cells.

PC12 细胞中大鼠尿激酶纤溶酶原激活剂受体启动子的表征。

• DOI: 10.1002/jnr.21296
• 发表时间: 2007
• 期刊: Journal of neuroscience research
• 影响因子: 4.2
• 作者: Su,Feng;Kozak,KatherineR;Herschman,Harvey;Reddy,SrinivasaT;Farias-Eisner,Robin
• 通讯作者: Farias-Eisner,Robin

Searching for depolarization-induced genes that modulate synaptic plasticity and neurotrophin-induced genes that mediate neuronal differentiation.

寻找调节突触可塑性的去极化诱导基因和介导神经元分化的神经营养蛋白诱导基因。

• DOI: 10.1023/a:1007546600535
• 发表时间: 2000
• 期刊: Neurochemical research
• 影响因子: 4.4
• 作者: Herschman,HR;Ferguson,GD;Feldman,JD;Farias-Eisner,R;Vician,L
• 通讯作者: Vician,L

NID67, a small putative membrane protein, is preferentially induced by NGF in PC12 pheochromocytoma cells.

NID67 是一种假定的小膜蛋白，在 PC12 嗜铬细胞瘤细胞中优先由 NGF 诱导。

• DOI: 10.1002/jnr.1058
• 发表时间: 2001
• 期刊: Journal of neuroscience research
• 影响因子: 4.2
• 作者: Vician,L;Silver,AL;Farias-Eisner,R;Herschman,HR
• 通讯作者: Herschman,HR