TAU ISOFORMS IN HUMAN BRAIN DISEASE AND TRANSGENIC MICE

描述：（逐字引用申请人摘要） 有证据表明，人类基因中编码 微管相关蛋白tau导致神经元死亡和痴呆。Tau 在中枢神经系统中以6种亚型存在，它们是 tau mRNA的选择性剪接。虽然有些突变发生在 在tau蛋白的编码序列中，几个突变似乎通过改变模式来起作用 tau mRNA的剪接，导致tau蛋白的比例发生变化， 在大脑中表达的同种型。这些变化似乎足以引起 一种迟发性神经元死亡，尤其是额叶和颞叶的神经元 皮层神经元和神经胶质中的Tau积累也发生在其中 尚未发现tau突变，如阿尔茨海默病，皮克氏病， 进行性核上性麻痹（Progressive Supranuclear Palsy）在后两种情况下， 在神经元和神经胶质中发生特异性tau同种型的积累。之甚少 目前已知的关于特定细胞中tau同种型表达的正常模式， 人类或动物大脑的神经元群体，甚至更少的信息， 可用于神经胶质中的tau同种型表达。这些知识对我们的 了解tau蛋白对神经元存活的重要性， 关于tau亚型模式变化在 神经元功能障碍和死亡。本申请中提出的工作将 涉及单克隆抗体的生产， 正常人神经元和胶质细胞中特异性tau蛋白亚型的表达 脑，在神经元和/或神经胶质中tau积累的痴呆的情况下，和 人类tau基因转基因小鼠的大脑中。

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.