Translational regulation in Alzheimer's Disease

阿尔茨海默病的转化调控

• 批准号: 6576435
• 负责人: LESLIE A KRUSHEL
• 金额: $ 7.57万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6576435
• 关键词: Alzheimer's disease; aging; amyloid proteins; brain circulation; cell line; disease /disorder etiology; endopeptidases; genetic regulation; genetic regulatory element; genetic translation; human genetic material tag; hypoxia; laboratory rat; messenger RNA; neurons; newborn animals; nucleic acid sequence; nucleic acid structure; pathologic process; presenilin; terminal nick end labeling; tissue /cell culture; transfection

Chronic hypofusion in the central nervous system, is hypothesized to predispose or lead to Alzheimer's Disease (AD). Increased expression and aggregation of an insoluble peptide, derived through the cleavage of the amyloid precursor protein (APP) by beta and gamma secretases, is thought to initiate plaque formation leading to cell death and the disease state. Hypoxia decreases protein synthesis by inhibiting the cap-binding/scanning mechanism for translation initiation, the major form of translation initiation. However, some mRNAs can also initiate translation in a cap-independent manner from internal ribosomal entry sites (IRESes) in the 5' leader. IRES dependent translation is unaffected or promoted by hypoxia. The hypothesis is that the 5' leaders of mRNAs encoding for proteins that contribute to the processing of APP, as well as APP, contain IRESes. In response to hypoxia, an increase in IRES dependent translation is predicted. Consequently, chronic hypoxia is hypothesized to lead to AD through a constant enhancement of IRESdependent translation with the concomitant increase of amyloid peptides. Accordingly, the proposed study will utilize neural cell lines and primary neurons grown in vitro as an assay system to answer the following questions: 1. Does the 5' leader of the APP mRNA and of the mRNAs encoding for proteins involved in the processing of APP including beta-secretases 1 and 2, and presenilins 1 and 2, contain IRESes? 2. Does hypoxia lead to an increase in IRES-dependent translation mediated by the AD-related 5' leaders? 3. What are the cis-elements in the 5' leaders of AD-related mRNAs that internally initiate translation in response to hypoxia? The proposed experiments will determine the mechanism of translation initiation of AD related mRNAs in response to hypoxia. The results will provide novel insights into the etiology of AD and present new avenues to explore for therapeutic intervention of individuals with AD or other vascular dementias.

假设中枢神经系统中的慢性低输血性会倾向或导致阿尔茨海默氏病（AD）。据认为，通过β和伽马分泌酶的淀粉样蛋白前体蛋白（APP）裂解不溶性肽的表达和聚集被认为会引发斑块形成，从而导致细胞死亡和疾病状态。缺氧通过抑制翻译起始的帽结合/扫描机制来降低蛋白质的合成，这是翻译起始的主要形式。但是，某些mRNA也可以从5'领导者的内部核糖体入口位点（IRESE）以无关的方式启动翻译。 IRES依赖性翻译不受缺氧的影响或促进。假设 是为蛋白质编码的5'领导者，这些蛋白质有助于APP的处理以及APP包含IRESES。响应缺氧，预计IRES依赖性翻译的增加。因此，假设慢性缺氧是通过依赖IRESEDERTIST翻译的恒定增强而导致AD导致AD的，并且淀粉样蛋白肽的随之增加。因此，拟议的研究将利用在体外生长的神经细胞系和原发性神经元作为一种测定系统来回答以下问题：1。APP mRNA的5'领导者以及编码用于应用程序处理的蛋白质的mRNA，包括β-分泌酶1和2，以及Presenilins 1和2和2，包含Ireses，包括β-分泌酶1和2 2。缺氧是否导致IRES依赖性翻译的增加，由AD相关的5'领导者介导？ 3。在响应缺氧的5'领导者5'领导者中的顺式元素是什么？ 提出的实验将确定与缺氧相关的AD相关mRNA的翻译启动机理。结果将为AD的病因提供新的见解，并提供新的途径，以探索AD或其他血管性痴呆症患者的治疗干预措施。