Transcriptional Responses in Neurodegenerative Diseases

描述（由申请人提供）：在人类神经退行性疾病中调节神经元细胞死亡的分子机制尚不清楚。一个可能在调节神经元细胞死亡中起作用的细胞内通路包括细胞周期转录因子的激活，从而改变基因表达和染色质结构。细胞周期调控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）。这些蛋白参与DNA损伤、氧化损伤和β肽诱导的细胞死亡。我们发现了FAC1和ZF87/MAZ转录因子与pRb_2F1之间的新的功能相互作用，并提出p53、pRb、E2F1、FAC1和ZF87/MAZ途径之间的相互作用在人类神经退行性疾病中调节细胞存活或死亡起关键作用。我们假设下游基因和染色质结构的表达改变导致神经退行性疾病中的神经元细胞死亡。我们的第一个特异性目标将在两种体外神经变性模型中直接测试这些转录因子的功能。第二个目标将在神经疾病的动物模型中测试这些转录调节因子调节神经退行性变的假设。影响细胞周期蛋白的特定药物将在该动物模型中检验其减缓疾病发作和提高生存率的能力。最后一个目标将检查转录因子在阿尔茨海默病（AD）和肌萎缩侧索硬化症（ALS）中的分布和功能，并确定它们在退行性神经元中的存在。体外和体内研究的结合将证明我们提出的模型的生理学相关性。我们提出的研究将大大增加我们对细胞周期转录因子在调节人类神经退行性疾病中神经元死亡中的作用的理解，并导致新的治疗策略来提高脑损伤和疾病期间神经元的存活率。

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.