Transcriptional Regulation of BACE and the Components of the gamma-Secretase Comp

BACE 和 γ-分泌酶复合物成分的转录调控

• 批准号: 7583967
• 负责人: Huaxi Xu
• 金额: $ 38.37万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7583967
• 关键词: AP40; Address; Affect; Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Binding; Binding Sites; Biogenesis; Biological; Brain; CD44 gene; CREB1 gene; Cells; Chemicals; Cleaved cell; Complex; Consensus; Data; Development; Down-Regulation; E-Cadherin; ErbB4 gene; Event; Gene Components; Gene Expression; Generations; Genes; Genetic Transcription; Hand; Histocompatibility Testing; Human; Hypoxia; Indium; Integral Membrane Protein; Light; Messenger RNA; Molecular Weight; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neuroglia; Neurons; PTGS2 gene; Pathogenesis; Pathologic; Pathway interactions; Peptides; Physiological; Play; Production; Promoter Regions; Property; Protein Overexpression; Proteins; Proteolysis; Rattus; Regulation; Reporting; Research; Research Personnel; Role; SP1 gene; Senile Plaques; Specificity; Substrate Specificity; TP53 gene; Therapeutic Intervention; Tissues; Transcription Factor AP-2 Alpha; Transcriptional Regulation; Translations; Variant; Yin; base; beta-site APP cleaving enzyme 1; cell type; cytokine; effective therapy; extracellular; gamma secretase; hypoxia inducible factor 1; in vivo; neuron apoptosis; neuron loss; nicastrin protein; notch protein; presenilin; programs; promoter; receptor; scaffold; secretase; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Overproduction of ¿-amyloid (A¿) is widely believed to trigger a cascade of neurodegeneration leading to Alzheimer's disease (AD). A¿ is proteolytically derived from ¿-amyloid precursor protein (APR) through sequential cleavages by ¿-secretase (BACE1) and ?-secretase complex (consisting of four components: presenilin, nicastrin, APH-1 and PEN-2). Much research effort has gone into studying regulation of secretase activity at the post-translation level, transcriptional regulation of gene expression of secretase components, the first step of any protein's biogenesis, has been much less explored. Recently we and others have characterized the basic promoter sequence for BACE1, presenilins, PEN-2 and APH-1, and several identified transcriptional factors. However, additional transcriptional factors and related regulatory mechanisms/pathways still remain to be identified. Questions such as how transcriptional events may differentially affect the secretase activity in different cell/tissue types, and the importance of the transcriptional regulation of the secretase components in AD pathogenesis are highly important and remain to be addressed. Based on the available information and our preliminary results, we propose to study the following aims: Specific Aim 1: to further characterize the transcriptional regulation of BACE1 by HIF/hypoxia and A¿, to determine the cell type specificity of promoter utilization for BACE1, and to correlate the importance of the transcriptional regulation of BACE1 gene in AD pathogenesis. We will (1) determine whether transcription of BACE1 is regulated by HIF-1 and whether HIF-1 deficiency affects BACE1 expression in vivo; (2) determine whether expression of BACE1 transcription factors (i.e. SP1 and HIF-1) and their activity are altered in AD brains; (3) determine transcriptional regulation of BACE1 in neuronal and non-neuronal cells; and (4) study a potential reciprocal regulation between A¿ and BACE1, i.e. to determine whether A¿ treatment regulates transcription of BACE1. Specific Aim 2: to define the promoter and transcriptional regulation of nicastrin, to determine the cell type specificity of promoter utilization for various ?-secretase component genes and their transcriptional regulation by A¿, and to correlate the importance of the transcriptional regulation of these genes in AD pathogenesis and in controlling the ?-secretase substrate specificity. We will (1) characterize promoter and transcriptional regulation of nicastrin gene; (2) determine whether the levels of transcription factors regulating expression of ?-secretase components are altered in AD brains; (3) define the cell type specific transcriptional regulation of genes encoding the four ?-secretase components; (4) determine whether A¿ treatment promotes the expression of ?-secretase components; and (5) determine the effects of transcriptional regulation on the ?-secretase activity to different substrates. Studying transcriptional regulation of these secretase components should be instrumental for developing effective therapies for AD.

描述（通过应用程序提供）：广泛认为 - 淀粉样蛋白（a。）的过量生产会触发一系列神经变性导致阿尔茨海默氏病（AD）的级联。蛋白水解是否是通过通过` - 分泌酶（BACE1）和？ - 分泌酶复合物（由四个成分组成的：Presenilin，Nicastrin，Nicastrin，Aph-1和Pen-2）的顺序裂解源自淀粉样蛋白前体蛋白（APR）。研究了在翻译后水平上的泌尿酶活性调节，分泌酶成分的基因表达的转录调控（任何蛋白质生物发生的第一步）的探索较少的探索较少的探索较少。最近，我们和其他人表征了BACE1，PRESENILINS，PEN-2和APH-1的基本启动子序列以及几个已鉴定的转录因子。但是，其他转录因素和相关的调节机制/途径仍有待确定。诸如转录事件如何不同地影响不同细胞/组织类型中的泌尿酶活性，以及​​泌尿酶成分在AD发病机理中的转录调节的重要性非常重要，并且仍有待解决的问题。基于可用信息和我们的初步结果，我们建议研究以下目的：特定目的1：进一步表征HIF/缺氧和A检验对BACE1的转录调控，以确定BACE1启动子利用的细胞类型特异性，并将Bace1 Gene在AD ADESOSESIS中的转录调节的重要性相关联。我们将（1）确定BACE1的转录是否受HIF-1的调节，以及HIF-1缺乏症是否影响体内的BACE1表达； （2）确定AD大脑中Bace1转录因子（即SP1和HIF-1）及其活性的表达是否改变； （3）确定神经元和非神经元细胞中BACE1的转录调节； （4）研究A和Bace1之间的潜在相互调节，即确定A处理是否调节BACE1的转录。具体目的2：定义尼卡斯特林的启动子和转录调控，以确定启动子利用的细胞类型特异性，用于各种？分泌酶成分基因及其通过A的转录调节，并将这些基因转录调控在AD病原体中的转录调节的重要性相关联，并控制 - 凝聚酶的特异性。我们将（1）表征启动子和尼卡斯特林基因的转录调节； （2）确定AD大脑中转录因子的水平是否改变； （3）定义编码四个？分泌酶成分的基因的细胞类型特异性转录调节； （4）确定a处理是否促进了 - 分泌酶成分的表达； （5）确定转录调控对 - 分泌酶活性对不同底物的影响。研究这些泌尿酶成分的转录调节应该有助于开发AD的有效疗法。