Cellular Nucleic Acid Binding Protein (CNBP) in Aging and Disease

细胞核酸结合蛋白 (CNBP) 在衰老和疾病中的作用

• 批准号: 7373045
• 负责人: Michael Paul Murphy
• 金额: $ 28.84万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7373045
• 关键词: Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein Precursor; Amyloid deposition; Animal Model; Automobile Driving; Binding Proteins; Binding Sites; Biochemical; Biological; Biological Models; Brain; Cell Culture System; Cell physiology; Cells; Cultured Cells; Data; Degenerative Disorder; Deposition; Development; Disease; Drug Industry; Enzymes; Event; Foundations; Future; Generations; Genes; Genetic; Health; Human; In Vitro; Inclusion Body Myositis; Introns; Investigation; Knowledge; Lead; Link; Mediator of activation protein; Messenger RNA; Muscular Dystrophies; Myopathy; Myotonic Dystrophy; Nucleotides; Pathogenesis; Pathology; Peptides; Peripheral; Process; Protein Binding; Protein Overexpression; Proteins; RNA; RNA-Binding Proteins; Rate; Regulation; Role; Site; Skeletal system; Staging; Testing; Therapeutic; Title; age related; amyloid peptide; base; beta-site APP cleaving enzyme 1; beta-site APP cleaving enzyme 2; design; human ZNF9 protein; improved; in vivo; inhibitor/antagonist; insight; knock-down; mouse model; normal aging; novel; peptide A; secretase

DESCRIPTION (provided by applicant): Investigation into the genetic causes of the muscular dystrophies has provided unique insights into the mechanisms of several disease processes. Type II Myotonic Dystrophy is caused by a large expansion in the ZNF9 gene, which encodes the single strand RNA binding protein CNBP (Cellular Nucleic Acid Binding Protein). Remarkably, we recently discovered that CNBP is involved in regulating the activity of ¿-secretase, the enzyme that produces the first cleavage event in the generation of the amyloid-¿ peptide (A¿). The progressive fibrillization and deposition of A¿ is widely believed to be the primary causal factor in the development of Alzheimer's disease. Importantly, the activity and protein levels of the major ¿-secretase enzyme in the brain (BACE1) increase in both Alzheimer's disease and in normal aging. This implicates regulators of BACE1 as potentially critical for the development of Alzheimer's disease, and our preliminary data suggest that CNBP may be one of these regulatory factors. Further, both BACE1 and the related peripheral enzyme BACE2 are both increased in Inclusion Body Myositis, an age-related, degenerative disease of the skeletal musculature considered by some to be a pathological cousin of Alzheimer's disease. Therefore, ¿-secretase activity itself is linked to at least two age-related diseases, making the question of understanding its regulation potentially important for human health. This proposal is designed to determine the role of CNBP as a critical protein for RNA regulation and as a potential mediator of degenerative disease via the regulation of ¿-secretase activity. This project focuses on three specific aims designed to (1) determine the mechanism through which CNBP regulates its targets, (2) determine what the normal function of CNBP is in the cell, and (3) determine what the role of CNBP is in disease. The project will advance through parallel stages of in vitro studies in biochemical and cell culture based model systems, up to studies in animal models of degenerative pathology. Understanding the mechanism through which CNBP operates will inform us about both basic processes in RNA regulation, and how they might go awry. These studies will lay the foundation for future advances into therapeutics to treat these diseases.

描述（由申请人提供）：对肌营养不良症遗传原因的调查为几种疾病过程的机制提供了独特的见解。 II 型强直性肌营养不良是由 ZNF9 基因的大量扩增引起的，该基因编码单链 RNA 结合蛋白 CNBP（细胞核酸结合蛋白）。值得注意的是，我们最近发现 CNBP 参与调节 β-分泌酶的活性，这种酶在淀粉样蛋白-β 肽 (A¿) 的生成过程中产生第一个裂解事件。人们普遍认为，进行性纤维化和Aβ沉积是阿尔茨海默病发展的主要原因。重要的是，在阿尔茨海默病和正常衰老过程中，大脑中主要β-分泌酶（BACE1）的活性和蛋白质水平都会增加。这表明 BACE1 的调节因子对于阿尔茨海默病的发展可能至关重要，我们的初步数据表明 CNBP 可能是这些调节因子之一。此外，BACE1 和相关外周酶 BACE2 在包涵体肌炎中均升高，包涵体肌炎是一种与年龄相关的骨骼肌肉组织退行性疾病，一些人认为它是阿尔茨海默病的病理表亲。因此，β-分泌酶活性本身与至少两种与年龄相关的疾病有关，这使得了解其调节问题对人类健康具有潜在的重要意义。该提案旨在确定 CNBP 作为 RNA 调节关键蛋白的作用，以及通过调节 ¿-分泌酶活性作为退行性疾病潜在介质的作用。该项目重点关注三个具体目标，旨在 (1) 确定 CNBP 调节其靶标的机制，(2) 确定 CNBP 在细胞中的正常功能，以及 (3) 确定 CNBP 在疾病中的作用。该项目将通过基于生化和细胞培养的模型系统的体外研究的平行阶段，直至退行性病理学动物模型的研究。了解 CNBP 的运作机制将使我们了解 RNA 调节的两个基本过程，以及它们如何可能出错。这些研究将为未来治疗这些疾病的疗法的进展奠定基础。