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

描述(由申请人提供)：对肌肉营养不良的遗传原因的调查为几个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编码单链RNA结合蛋白CNBP(细胞核酸结合蛋白)的ZNF9基因大量扩增引起的。值得注意的是，我们最近发现CNBP参与调节分泌酶的活性，该酶在淀粉样多肽(A？)的产生中产生第一个切割事件。A？的进行性纤维化和沉积被广泛认为是阿尔茨海默病发展的主要原因。重要的是，大脑中的主要分泌酶(BACE1)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。这意味着BACE1的调节因子可能对阿尔茨海默病的发展起着关键作用，我们的初步数据表明CNBP可能是这些调节因子之一。此外，BACE1和相关的外周酶BACE2在包涵体肌炎中都会增加，这是一种年龄相关的骨骼肌肉退行性疾病，一些人认为它是阿尔茨海默病的病理近亲。因此，分泌酶活性本身与至少两种与年龄相关的疾病有关，这使得了解其调控对人类健康具有潜在的重要意义。这项建议旨在确定CNBP作为RNA调节的关键蛋白质和通过调节分泌酶活性作为退行性疾病的潜在介体的作用。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。该项目将通过生化和基于细胞培养的模型系统的体外研究的平行阶段，直到退行性病理的动物模型研究。了解CNBP的运作机制将让我们了解RNA调控的基本过程，以及它们可能会出现的错误。这些研究将为未来治疗这些疾病的疗法的进展奠定基础。

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.