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: 7848413
• 负责人: Michael Paul Murphy
• 金额: $ 2.42万
• 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 2009-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848413
• 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 Culture Techniques; Cell physiology; 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; Proteins; RNA; RNA-Binding Proteins; Regulation; Role; Site; Staging; Testing; Therapeutic; age related; 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; overexpression; secretase; skeletal

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研究为几种疾病过程的机制提供了独特的见解。II型肌强直性营养不良症是由ZNF 9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<$-分泌酶的活性，该酶在淀粉样肽（A <$）的生成中产生第一个切割事件。广泛认为，A？的进行性纤维化和沉积是阿尔茨海默病发展的主要原因。重要的是，大脑中主要的分泌酶（BACE 1）的活性和蛋白质水平在阿尔茨海默病和正常衰老中都会增加。这表明BACE 1的调节因子对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，BACE 1和相关的外周酶BACE 2在包涵体肌炎中均增加，包涵体肌炎是一种与年龄相关的骨骼肌肉系统退行性疾病，被一些人认为是阿尔茨海默病的病理表亲。因此，- 分泌酶活性本身与至少两种与年龄有关的疾病有关，因此了解其调节对人类健康具有潜在的重要性。该提案旨在确定CNBP作为RNA调节的关键蛋白质以及通过调节β-分泌酶活性作为退行性疾病的潜在介质的作用。该项目侧重于三个具体目标，旨在（1）确定CNBP调节其靶点的机制，（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。该项目将通过生物化学和细胞培养为基础的模型系统的体外研究的平行阶段，以研究退行性病理学的动物模型。了解CNBP的运作机制将使我们了解RNA调控的基本过程以及它们如何出错。这些研究将为未来治疗这些疾病的治疗方法的发展奠定基础。