Transcriptional Responses in Neurodegenerative Diseases

神经退行性疾病的转录反应

• 批准号: 6731286
• 负责人: ROBERT P BOWSER
• 金额: $ 26.1万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6731286
• 关键词: Alzheimer' s disease; DNA damage; amyotrophic lateral sclerosis; brain injury; cell cycle; cell cycle proteins; chromatin immunoprecipitation; confocal scanning microscopy; gel mobility shift assay; gene expression; genetically modified animals; human tissue; laboratory mouse; neural degeneration; oxidative stress; p53 gene /protein; polymerase chain reaction; protein localization; protein protein interaction; retinoblastoma protein; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): The molecular mechanisms that regulate neuronal cell death during human neurodegenerative diseases remain unclear. One intracellular pathway that may function in regulating neuronal cell death includes the activation of cell cycle transcription factors that alter gene expression and chromatin structure. Key protein components of the cell cycle regulated death of neurons include p53, E2F1 and the retinoblastoma protein (pRb). These proteins participate in cell death induced by DNA damage, oxidative injury and the Abeta peptide. We have identified novel functional interactions between the FAC1 and ZF87/MAZ transcription factors with pRb_2F1 and propose that interactions between p53, pRb, E2F1, FAC1, and ZF87/MAZ pathways play a pivotal role to regulate cell survival or death during human neurodegenerative diseases. We hypothesize that altered expression of downstream genes and chromatin structure leads to neuronal cell death in neurodegenerative diseases. Our first Specific Aim will directly test the function of these transcription factors in two in vitro models of neurodegeneration. The second Aim will test the hypothesis that these transcriptional regulators regulate neurodegeneration in an animal model of neurologic disease. Specific drugs that affect cell cycle proteins will be examined for their ability to slow disease onset and increase survival in this animal model. The last Aim will examine the distribution and function of transcription factors during Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) and to determine their presence in degenerating neurons. The combination of in vitro and in vivo studies will demonstrate the physiologic relevancy for our proposed model. Our proposed studies will greatly increase our understanding of the role that cell cycle transcription factors play in regulating neuronal death during human neurodegenerative diseases and lead to novel therapeutic strategies to enhance neuronal survival during brain injury and disease.

描述（由申请人提供）：人类神经退行性疾病期间调节神经元细胞死亡的分子机制仍不清楚。一种可能在调节神经元细胞死亡中发挥作用的细胞内途径包括激活改变基因表达和染色质结构的细胞周期转录因子。细胞周期调节神经元死亡的关键蛋白成分包括 p53、E2F1 和视网膜母细胞瘤蛋白 (pRb)。这些蛋白质参与 DNA 损伤、氧化损伤和 Abeta 肽诱导的细胞死亡。我们已经确定了 FAC1 和 ZF87/MAZ 转录因子与 pRb_2F1 之间的新功能相互作用，并提出 p53、pRb、E2F1、FAC1 和 ZF87/MAZ 通路之间的相互作用在人类神经退行性疾病期间调节细胞生存或死亡中发挥着关键作用。我们假设下游基因和染色质结构表达的改变导致神经退行性疾病中神经元细胞死亡。我们的第一个具体目标将直接测试这些转录因子在两种体外神经退行性变模型中的功能。第二个目标将检验这些转录调节因子在神经疾病动物模型中调节神经退行性变的假设。将检查影响细胞周期蛋白的特定药物在该动物模型中减缓疾病发作和提高存活率的能力。最后一个目标将检查阿尔茨海默病（AD）和肌萎缩侧索硬化症（ALS）期间转录因子的分布和功能，并确定它们在退化神经元中的存在。体外和体内研究的结合将证明我们提出的模型的生理相关性。我们提出的研究将极大地增进我们对细胞周期转录因子在人类神经退行性疾病期间调节神经元死亡中所起作用的理解，并产生新的治疗策略来增强脑损伤和疾病期间神经元的存活。