Genetic Regulation of Complex Neurological Disease

复杂神经系统疾病的基因调控

• 批准号: 7810175
• 负责人: WAYNE N. FRANKEL
• 金额: $ 37.31万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7810175
• 关键词: Absence Epilepsy; Accounting; Adult; Age; Animal Model; Autoimmune Process; Biological; Biology; Brain; Brain Diseases; Collaborations; Complement; Complex; Development; Diet; Disease; Disease model; Electrophysiology (science); Environment; Epilepsy; Funding; Future; Gene Expression; Genes; Genetic; Goals; Heart Diseases; Hippocampus (Brain); Investigation; Learning; Maintenance; Malignant Neoplasms; Medical; Molecular; Motor Seizures; Mutant Strains Mice; Mutation; Nature; Neurons; Phenotype; Public Health; Publishing; Recovery; Regulation; Research; Seizures; Slice; Synapses; Tonic - clonic seizures; Tonic-Clonic Epilepsy; United States National Institutes of Health; base; excitatory neuron; inhibitory neuron; insight; mutant; nervous system disorder; patch clamp; programs; public health relevance; tool

DESCRIPTION (provided by applicant): The goal of this Competitive Revision application (NOT-OD-09-058 - NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications) is to complement our current program (NS061971) to study the molecular basis of complex seizure disorder in Brunol4 mutant mice, by examining the cellular basis of the seizure phenotypes using conditional gene expression and electrophysiology. We already published that Brunol4 heterozygous mutants have limbic and tonic-clonic seizures and a low seizure threshold, and homozygous mutants also have spontaneous absence seizures. Using temporal conditional deletion, we recently determined that it is sufficient to delete Brunol4 at 7 wks of age to lower seizure threshold and to produce spontaneous limbic and tonic-clonic convulsions. This was invaluable information to have as it suggests that future investigation into the biological mechanism can focus on adult, maintenance functions of Brunol4 rather than development per se. In addition, by using spatial conditional deletion, we also determined that removing of Brunol4 from cortical and hippocampal excitatory neurons may account for a portion, but not all, of the convulsive seizure phenotype-providing further biological insight into the complexity. In the first part of the competitive revision, we will complete the conditional studies by examining the effects of deleting Brunol4 from inhibitory neurons. We will also assess the effects of compound conditional deletion by combining two different cre drivers (i.e. excitatory and inhibitory). In the second part, we will perform patch-clamp electrophysiological recordings of neurons in germline and conditional mutants, to give further insight into effect of the mutation on synaptic activity at the cellular level. This will be in collaboration with our colleague Dr. Zhang, an expert in brain slice electrophysiology. This extension of the currently funded program, in which the aims are entirely molecular in nature, will complete our initial picture of the 'biology' of the complex seizure disorder in this animal model. In addition, we are excited about the possibility of using this as an opportunity to add new tools to our research abilities. These will be critical both for rounding-out the Brunol4 program, and for providing opportunities for mechanistic insight into our other disease models in the future. PUBLIC HEALTH RELEVANCE: The most common medical conditions, such as heart disease, cancer, autoimmune and brain disorders, are often genetically complex, influenced by the interaction of multiple genes with other factors such as diet and environment. This complexity makes it a challenge to study and to understand the causes of common disease. In this program we will study the function of a gene, called Brunol4, which mimics a genetically complex "excitability" disorder of the brain by causing the misexpression of many other genes. Learning how Brunol4 functions at the molecular and cellular level will help us to understand how and why genes are coordinately regulated in the brain and may provide new entry points for future therapies.

描述（由申请人提供）：本竞争性修订申请（no - od -09-058 - NIH宣布为竞争性修订申请提供恢复法案基金）的目标是补充我们当前的项目（NS061971），通过使用条件基因表达和电生理学检查癫痫表型的细胞基础，研究Brunol4突变小鼠复杂癫痫发作障碍的分子基础。我们已经发表了Brunol4杂合突变体有边缘和强直阵挛发作和低发作阈值，纯合突变体也有自发性失神发作。使用时间条件删除，我们最近确定在7周龄时删除Brunol4足以降低癫痫发作阈值并产生自发的边缘和强直阵挛性抽搐。这是非常宝贵的信息，因为它表明未来对生物学机制的研究可以集中在成年，维持功能的Brunol4，而不是发展本身。此外，通过使用空间条件删除，我们还确定，从皮层和海马兴奋性神经元中去除Brunol4可能解释了抽搐发作表型的一部分，但不是全部，这为复杂性提供了进一步的生物学见解。在竞争性修订的第一部分，我们将通过检查从抑制性神经元中删除Brunol4的影响来完成条件研究。我们还将通过结合两种不同的cre驱动因素（即兴奋性和抑制性）来评估复合条件缺失的影响。在第二部分中，我们将对种系和条件突变体的神经元进行膜片钳电生理记录，以进一步了解突变对细胞水平突触活动的影响。这将与我们的同事张博士合作，他是脑切片电生理学的专家。目前资助的项目的扩展，其目的完全是分子性质的，将完成我们在动物模型中复杂癫痫发作障碍的“生物学”的初步图景。此外，我们很高兴能够利用这个机会为我们的研究能力增加新的工具。这对于完善Brunol4项目至关重要，并为未来我们对其他疾病模型的机制洞察提供了机会。