Genetic Regulation of Seizure-Induced Neurogenesis

癫痫引起的神经发生的基因调控

• 批准号: 6805244
• 负责人: PAULA E SCHAUWECKER
• 金额: $ 18.21万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6805244
• 关键词: biotechnology; brain injury; cerebral ventricles; dentate gyrus; epilepsy; functional /structural genomics; genetic regulation; genetic strain; genotype; inbreeding; kainate; laboratory mouse; nervous system regeneration; neurogenetics; olfactory lobe; prosencephalon

DESCRIPTION (provided by applicant): The goal of this proposal is to determine whether allelic variation of excitotoxic cell death-vulnerable or -resistant inbred mouse strains modulates basal and seizure-induced adult forebrain neurogenesis. Recent studies suggest that aberrant regulation of persistent neurogenesis in the adult contributes to hippocampal hyperexcitability and cognitive problems associated with temporal lobe epilepsy. Despite the intense interest in persistent forebrain neural stem cells and their potential utility for brain repair therapies, little is known about the regulation of neurogenesis in the intact and injured brain. We (Dr. J. Parent) and others recently have found that experimental seizures increase neurogenesis and induce ectopic neuroblast migration in the adult rodent forebrain. The molecular mechanisms underlying these effects remain unknown. We (Dr. P. Schauwecker) have also discovered that certain inbred strains of mice differ markedly in the extent of cell death after kainic acid (KA)-induced status epilepticus (SE). By combining two cross disciplinary approaches to address altered network function in epileptogenesis, we plan to investigate the influence of genetic variation and cell death on adult neurogenesis. This collaborative proposal, a response to the program announcement for Exploratory awards in Epilepsy Research for Junior Investigators, will test two hypotheses: (1) Adult murine dentate gyrus and subventricular zone (SVZ) neurogenesis are influenced by allelic variation; and (2) Tissue injury is required to stimulate neurogenesis and ectopic neuroblast migration in the adult mouse forebrain. The specific aims are: 1) To determine whether basal adult hippocampal neurogenesis varies in mice resistant (C57BL/6) or susceptible (FVB/N) to seizure-induced cell death; 2) To establish whether SVZ-olfactory bulb neurogenesis is differentially regulated in adult C57BL/6 and FVB/N mice; 3) To determine whether seizure-induced dentate gyrus neurogenesis is triggered by injury using our model of genetically-defined murine strains; and 4) To determine whether seizure-induced SVZ neurogenesis or ectopic neuroblast migration differs between KA-induced cell death susceptible or resistant mice. The results of this collaboration will provide further insight into novel stem cell treatments for epilepsy and aid in determining effective preventative strategies and rational therapeutic designs for this neurological disorder.

描述（由申请人提供）：该提案的目的是确定兴奋性细胞死亡可杀死或抗性的近交小鼠菌株的等位基因变异是否会调节基础和癫痫发作诱导的成年前脑神经发生。 最近的研究表明，成年人中对持续性神经发生的异常调节有助于与颞叶癫痫相关的海马过度兴奋性和认知问题。 尽管对持续的前脑神经干细胞及其对脑修复疗法的潜在效用非常感兴趣，但对完整和受伤大脑中神经发生的调节知之甚少。 我们（J. Parent博士）和其他人最近发现，实验性癫痫发作会增加神经发生并诱导成年啮齿动物前脑的异位神经细胞迁移。 这些作用背后的分子机制仍然未知。 我们（P. schauwecker博士）还发现，在海藻酸（KA）诱导的癫痫持续状态（SE）后，某些小鼠的近交菌株在细胞死亡的程度上明显不同。 通过结合两种跨学科方法来解决癫痫发生中网络功能的改变，我们计划研究遗传变异和细胞死亡对成人神经发生的影响。 这项合作提案是对初级研究人员癫痫研究计划的计划公告的回应，将检验两个假设：（1）成年成年鼠齿回和室内脑室（SVZ）神经发生受等位基因变异的影响； （2）需要组织损伤来刺激成年小鼠前脑中神经发生和异位神经细胞迁移。 具体目的是：1）确定基础成人海马神经发生在耐药性（C57BL/6）或易感（FVB/N）中脱发诱导的细胞死亡的小鼠中是否有变化； 2）确定在成年C57BL/6和FVB/N小鼠中是否差异地调节了SVZ-FOLCACTORY BULB神经发生； 3）确定使用我们的遗传定义的鼠菌株模型损伤触发癫痫发作诱导的齿状回神经发生。 4）为了确定癫痫发作诱导的SVZ神经发生或异位神经细胞迁移是在KA诱导的细胞死亡易感或抗性小鼠之间的不同。 这种合作的结果将为癫痫病的新型干细胞治疗提供进一步的见解，并有助于确定这种神经系统疾病的有效预防策略和合理的治疗设计。