TAU ISOFORMS IN HUMAN BRAIN DISEASE AND TRANSGENIC MICE

描述：(逐字摘自申请者的摘要)有一个不断增长的身体 有证据表明人类基因编码的突变 微管相关蛋白tau导致神经元死亡和痴呆。陶氏 在中枢神经系统中以6种亚型存在，这6种亚型是 Tau基因的选择性剪接。尽管一些突变发生在 Tau的编码序列，几个突变似乎通过改变模式而起作用 导致tau的比例发生改变。 在大脑中表达的异构体。这些变化似乎足以导致 迟发性神经元死亡，尤指额叶和颞叶的神经元 大脑皮层。Tau在神经元和神经胶质细胞中的积聚也发生在以下疾病中 目前还没有发现tau基因突变，如阿尔茨海默病、皮克氏病 疾病和进行性核上性麻痹。在后两种情况下， 特定tau亚型的积累发生在神经元和神经胶质细胞中。小才是 目前已知的tau异构体在特定组织中的正常表达模式 人类或动物大脑的神经元种群，而更少的信息是 可在胶质细胞中表达tau异构体。这样的知识对我们的 了解tau对神经元存活和发育的重要性 关于tau异构体模式变化在脑内的作用的可检验假说 神经元功能障碍和死亡。本申请中提出的工作将 涉及生产单抗，以允许检测 特异性tau亚型在正常人神经元和神经胶质细胞中的表达 大脑，在tau在神经元和/或神经胶质细胞中积聚的痴呆病例中，以及 在转人tau基因的小鼠的大脑中。

DESCRIPTION: (Verbatim from the Applicant's Abstract) There is a growing body of evidence that mutations in the human gene encoding the microtubule-associated protein tau result in neuronal death and dementia. Tau is present in the central nervous system in 6 isoforms, which are products of alternative splicing of the tau mRNA. Although some mutations occur in the coding sequence of tau, several mutations appear to act by changing the pattern of splicing of the tau mRNA, resulting in changes in the ratio of the tau isoforms expressed in the brain. These changes appear to be sufficient to cause a late-onset neuronal death, especially in neurons of the frontal and temporal cortex. Tau accumulation in neurons and glia also occurs in diseases in which no tau mutations have yet been found, such as Alzheimer's disease, Pick's disease and Progressive Supranuclear Palsy. In the latter two conditions, accumulation of specific tau isoforms occurs in neurons and glia. Little is currently known about the normal pattern of tau isoform expression in specific neuronal populations of the human or animal brain, and even less information is available on tau isoform expression in glia. Such knowledge is essential to our understanding of the importance of tau for neuronal survival, and to develop testable hypotheses regarding the role of tau isoform pattern changes in neuronal dysfunction and death. The work proposed in this application will involve the production of monoclonal antibodies that will allow examination of the expression of specific tau isoforms in neurons and glia of the normal human brain, in cases of dementia with tau accumulation in neurons and/or glia, and in the brains of mice transgenic for human tau.