DYRK TRANSGENIC MICE AS A MODEL FOR DOWN SYNDROME

DYRK 转基因小鼠作为唐氏综合症模型

• 批准号: 6388255
• 负责人: GABRIELLA D'ARCANGELO
• 金额: $ 8.34万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6388255
• 关键词: Downs syndrome; developmental neurobiology; disease /disorder model; gene expression; genetically modified animals; laboratory mouse; model design /development; neuroanatomy; neurogenesis

DESCRIPTION: (adapted from applicant's abstract) Down Syndrome is the most common genetic disease associated with mental retardation, affecting about 1 in every 800 live births. The syndrome results from triplication of chromosome 21 or a segment of it, and it includes facial abnormalities, heart disease, increased frequency of leukemia, early-onset Alzheimer's disease and mental retardation. The latter is associated with decreased neuronal number and reduced complexity of neuronal processes in many regions of the brain. The entire spectrum of Down Syndrome abnormalities likely results from overexpression of several genes located in a critical region on chromosome 21q22.2, and it is thus a complex trait. However, individual aspects of the syndrome may be attributable to one or few genes. Recently, the human homologue of Drosophila minibrain, also known as Dyrk, has been mapped to the Down Syndrome critical region. Mutant minibrain flies have a reduced number of brain cells, suggesting that the mutated gene encodes a protein involved in neurogenesis. Mammalian Dyrks are dual specificity protein kinases with extensinve similarities to Drosophila Minibrain and to the yeast Yak1 protein kinase involved in cell division. Injection of a YAC containing genomic sequences including the Dyrk gene in transgenic mice causes altered neurogenesis and cognitive impairment, suggesting that Dyrk is involved in the brain abnormalities associated with Down Syndrome. To understand whether Dyrk plays a role in the developmental neuropathology underlying the mental retardation aspect of Down Syndrome, the investigators plan to first analyze in detail the normal pattern of expressionand activity of Dyrk in the developing mouse brain. Second, they will create transgenic mice that transiently and specifically express elevated levels of Dyrk in the proliferative zone of the developing brain. Finally, they will analyze in detail the brains of these mice to ascertain whether reduction in the number of neuronal cells, or other defects reminiscent of Down Syndrome, have occurred as a result of Dyrk overexpression in the brain during the period of neurogenesis. Their transgenic mice may serve as a novel animal model to investigate the molecular basis of mental retardation in Down Syndrome.

描述：(改编自申请者摘要)唐氏综合症是最常见的 与精神发育迟滞有关的常见遗传病，影响约1/4 每800个活产婴儿。该综合征是由21号染色体的三倍体引起的 或其中一部分，包括面部畸形，心脏病， 白血病、早发性阿尔茨海默病和精神分裂症的发生率增加 智力迟缓。后者与神经元数量减少和 降低了大脑许多区域的神经元过程的复杂性。这个 唐氏综合征异常的整个谱系可能是由 位于染色体关键区域的几个基因的过表达 21q22.2，因此这是一个复杂的性状。然而，在某些方面， 综合症可能归因于一个或几个基因。最近，人类同源物 果蝇的迷你大脑，也被称为Dyrk，已经被映射到Down 证候临界区。突变的迷你大脑苍蝇的大脑数量减少 细胞，这表明突变的基因编码了一种参与 神经发生。哺乳动物Dyrks是具有双重特异性的蛋白激酶 延伸素与果蝇小脑和酵母Yak1蛋白的相似性 参与细胞分裂的激酶。注射含基因组的YAC 转基因小鼠中包括Dyrk基因的序列发生改变 神经发生和认知障碍，表明Dyrk参与了 与唐氏综合症相关的脑部异常。 了解Dyrk是否在发育性神经病理学中起作用 在唐氏综合症精神发育迟滞的背后，研究人员 计划首先详细分析正常的表情和活动模式 在发育中的小鼠大脑中的Dyrk。其次，他们将创造转基因小鼠 短暂而明确地表达Dyrk在 发育中的大脑的增殖区。最后，他们将分析 详述这些小鼠的大脑，以确定是否减少了 神经细胞，或其他让人联想到唐氏综合症的缺陷，发生在 这是神经发生期间Dyrk在大脑中过度表达的结果。 他们的转基因小鼠可以作为一种新的动物模型来研究 唐氏综合征精神发育迟滞的分子基础