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）：阿尔茨海默氏病（AD）是全球的AA病例。最近的证据表明，癫痫发作不仅是偶然的，而且可能在疾病计划的认知下降中起着积极的作用这样的提议着重于海马中癫痫发作的分子和变化，这是一种受AD影响的大脑区域的严重程度，利用转基因小鼠表达了人类淀粉样蛋白蛋白的转基因小鼠，揭示了Thibibibibibibibibibibibibibipipe与淀粉样蛋白菌斑的沉积相比，这种发现特别有趣。因此，ΔFOSB可能在长期表观遗传基因调节中起重要作用，我们对海马狂欢的ΔFOSB的初步研究两个重要的基因靶标：CFOS和Calbindin-D28K。生存，它们对ΔFOSB的调节支持ΔFOSB的假设 在慢性神经元中过度刺激的状态中有助于神经保护和突触。体内功能障碍和2）调节靶基因，以及在体外的神经保护作用中起作用的作用。