Role of deltaFosB in Neuronal and Cognitive Function

deltaFosB 在神经元和认知功能中的作用

• 批准号: 9052038
• 负责人: Jason You
• 金额: $ 4.57万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-05 至 2018-03-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9052038
• 关键词: Accounting; Affect; Age-Months; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Antiepileptic Agents; Area; Biological Assay; Brain; Brain region; Calcium-Binding Proteins; Cell Nucleus; Cell Survival; Chronic; Cognition; Cognitive deficits; Complication; Dementia; Deposition; Development; Disease; Disease Progression; Electroencephalography; Epigenetic Process; Epilepsy; Exhibits; Figs - dietary; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Targeting; General Population; Genes; Glutamates; Goals; HDAC1 gene; Half-Life; Hippocampus (Brain); Human Amyloid Precursor Protein; Immediate-Early Genes; Impact Seizures; Impaired cognition; Impairment; In Vitro; Incidence; Investigation; Knowledge; Laboratories; Link; Memory; Memory Loss; Modeling; Molecular; Mus; Mutation; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Patients; Peptide Fragments; Play; Proteins; Quality of life; Regulation; Regulator Genes; Role; Seizures; Senile Plaques; Staging; Synapses; Synaptic plasticity; System; Testing; Toxic effect; Transgenic Mice; Transgenic Organisms; Viral Vector; Work; abeta accumulation; calbindin; calbindin-D28K; cognitive function; epigenetic regulation; excitotoxicity; improved; in vivo; insight; interest; knock-down; mouse model; nervous system disorder; neuroprotection; novel; novel therapeutics; overexpression; public health relevance; spatial memory; transcription factor; treatment strategy

 DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a neurodegenerative disease that accounts for approximately 50-80% of dementia cases worldwide. The disease is characterized by progressive cognitive decline and severe memory loss. As current therapies for AD offer limited benefit if any, the need to better understand the mechanisms of cognitive decline in AD cannot be overstated. The key finding that AD is associated with seizures may provide valuable insight into these mechanisms. Recent evidence suggests that seizures in AD are not just incidental, but may play an active role in contributing to cognitive decline early in disease progression. Consistent with this, treatment of both AD patients and AD mouse models with antiepileptics improves cognitive function. Therefore, understanding how seizures contribute to cognitive decline may open an avenue to discover novel therapies that can mitigate cognitive deficits and improve quality of life for AD patients, as well as for patients wih other neurological disorders accompanied by seizures. As such, this proposal focuses on the molecular and cellular changes induced by seizures in the hippocampus, a brain region severely affected by AD. Preliminary studies utilizing transgenic mice that express the human amyloid precursor protein (APP) carrying disease-linked mutations revealed that these mice exhibited epileptic spike activity and seizures as early as two months of age, just prior to the onset of cognitive deficits and significantly earlier than amyloid plaque deposition. Furthermore, examination of hippocampi in these mice showed markedly increased expression of a transcription factor ΔFosB. This finding was particularly interesting considering that the increas in ΔFosB expression corresponded with both epileptic activity in the brain as well as cognitive impairment. Previous studies of ΔFosB in other brain regions demonstrated that this transcription factor has an unusually long half-life (on the order of weeks) and interacts with HDACs. As such, ΔFosB may play an important role in long-term epigenetic gene regulation. Notably, our preliminary investigation of ΔFosB in the hippocampus revealed two important gene targets: cFos and calbindin-D28k. Since these genes play important functions in synaptic plasticity as well as cell survival, their regulation by ΔFosB supports the hypothesis that ΔFosB contributes to both neuroprotection and synaptic dysfunction during states of chronic neuronal hyperexcitation. Therefore, the goals of this proposal are to elucidate the functions of ΔFosB in AD and other seizure-related disorders. The Aims of this proposal are to 1) evaluate whether expression of ΔFosB is sufficient to drive gene expression changes and cognitive dysfunction in vivo and 2) investigate the mechanisms by which ΔFosB epigenetically regulates target genes, and the role that ΔFosB plays in neuroprotection in vitro. Results from these studies will pave the way for the development of much-needed novel therapies to improve cognitive function in AD and other seizure-related disorders.

 描述（由申请人提供）：阿尔茨海默病（AD）是一种神经退行性疾病，约占全球痴呆病例的 50-80%，该疾病的特点是进行性认知能力下降和严重的记忆丧失，因为目前的 AD 治疗效果有限。如果有的话，更好地了解 AD 认知衰退机制的必要性无论如何强调都不为过。AD 与癫痫发作相关的关键发现可能为了解这些机制提供有价值的见解。最近的证据表明，AD 癫痫发作不仅是偶然的，而且可能是偶然的。与此相一致的是，用抗癫痫药治疗 AD 患者和 AD 小鼠模型可以改善认知功能，因此，了解癫痫如何导致认知衰退可能为发现新疗法开辟道路。可以减轻 AD 患者以及患有其他伴有癫痫发作的神经系统疾病的患者的认知缺陷并提高生活质量，因此，该提案重点关注海马体（一个严重的大脑区域）癫痫发作引起的分子和细胞变化。利用表达携带疾病相关突变的人类淀粉样前体蛋白 (APP) 的转基因小鼠进行的初步研究表明，这些小鼠早在两个月大时即在认知缺陷出现之前就表现出癫痫尖峰活动和癫痫发作。并且明显早于淀粉样斑块沉积。此外，对这些小鼠的海马体的检查显示转录因子ΔFosB的表达显着增加，考虑到ΔFosB表达的增加与此相对应。先前对大脑其他区域的 ΔFosB 的研究表明，该转录因子具有异常长的半衰期（大约数周），并且与 HDAC 相互作用，因此，ΔFosB 可能发挥作用。值得注意的是，我们对海马中 ΔFosB 的初步研究揭示了两个重要的基因靶标：cFos 和 calbindin-D28k，因为这些基因发挥着重要作用。在突触可塑性和细胞存活中发挥作用，它们受 ΔFosB 的调节支持了以下假设： 在慢性神经元过度兴奋状态下有助于神经保护和突触功能障碍因此，本提案的目标是阐明 ΔFosB 在 AD 和其他癫痫相关疾病中的功能。本提案的目的是 1) 评估是否表达。 ΔFosB足以驱动体内基因表达变化和认知功能障碍，2）研究ΔFosB表观遗传调节靶基因的机制，以及ΔFosB所发挥的作用这些研究的结果将为开发急需的新疗法铺平道路，以改善 AD 和其他癫痫相关疾病的认知功能。