MOUSE MODEL OF RETARDATION IN DOWNS SYNDROME

唐氏综合症小鼠发育迟缓模型

• 批准号: 6521277
• 负责人: ZYGMUNT GALDZICKI
• 金额: $ 23.21万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6521277
• 关键词: AMPA receptors; Downs syndrome; NMDA receptors; biological models; biological signal transduction; cAMP response element binding protein; computer data analysis; cyclic AMP; electrophysiology; gene expression; hippocampus; laboratory mouse; long term potentiation; mental retardation; model design /development; molecular pathology; neuropathology; neurophysiology; phosphorylation; protein kinase A; protein kinase C; sectioning; voltage /patch clamp; voltage gated channel; western blottings; AMPA receptors; Downs syndrome; NMDA receptors; biological models; biological signal transduction; cAMP response element binding protein; computer data analysis; cyclic AMP; electrophysiology; gene expression; hippocampus; laboratory mouse; long term potentiation; mental retardation; model design /development; molecular pathology; neuropathology; neurophysiology; phosphorylation; protein kinase A; protein kinase C; sectioning; voltage /patch clamp; voltage gated channel; western blottings

DESCRIPTION (Provided by applicant): Down syndrome (DS) or trisomy 21 (Ts21) is caused by the presence of three copies of chromosome 21, and is the most frequent genetic cause of mental retardation. The Ts65Dn trisomic mouse has recently been developed and is trisomic only for the segment of murine chromosome 16 that is homologous to the segment of human chromosome 21 thought to contribute to mental retardation and vulnerability to Alzheimer disease in DS. This mouse demonstrates abnormal behavior and is impaired in various learning paradigms. We demonstrated that long-term potentiation (LTP) and long- term depression (LTD) decrease and increase respectively in the CAl region of the Ts65Dn mouse of Ts65Dn mouse hippocampus. The objective of this proposal is to find mechanisms that cause the abnormal LTP and LTD. Three specific aims are proposed to test that abnormal LTP and LTD are due to changes in signal transduction pathways mediated by protein kinase A (PKA) and/or protein kinase C (PKC) that would cause posttranslational changes in voltage-dependent Na+, Ca2+ channels and NMDA-, AMPA-glutamate receptors and cause changes in synaptic activity in the hippocampus. Aim#1: Determine PKA pathway activity in Ts65Dn hippocampus in relation to LTP and LTD paradigm. Determine expression of phosphorylated CREB. Aim #2:PKC activity in Ts65Dn hippocampus in relation to LTP and LTD paradigm. Determine expression pattern of PKC isoforms. Aim #3:Determine the expression and posttranslational modification of voltage dependent Na+, Ca2+ channels and NMDA -, AMPA- glutamate receptors using nucleated patch-clamp recording technique and binding studies. The impact of PKC isoforms will be tested in cell lines that permanently over express Na+ channel, Ca2+ channels, NMDA and AMPA receptors. Signal transduction impairments in genetic model of DS will determine important targets for treatment of mental retardation. In addition the outcome of this research will include further understanding of the role of PKA and PKC and voltage-dependent channels and NMDA- and AMPA-receptors in the mechanisms that are behind LTP and LTD.

描述（由申请人提供）：唐氏综合症（DS）或三体症（TS21）为 由三副染色体21的存在引起，是最多的 经常出现智力障碍的遗传原因。 TS65DN Trisomic鼠标具有 最近开发了，仅适用于鼠段 与人类染色体21思想段同源的16染色体 为智力低下和对阿尔茨海默氏病的脆弱性做出贡献 DS。该小鼠表现出异常行为，并在各种 学习范式。我们证明了长期增强（LTP）和长期 术语抑郁（LTD）分别减少和增加 TS65DN小鼠海马的TS65DN小鼠。该提议的目的是 找到引起异常LTP和LTD的机制。三个具体目标是 提议测试异常LTP和LTD是由于信号的变化而引起的 蛋白激酶A（PKA）和/或蛋白激酶介导的转导途径 C（PKC）会导致电压依赖性Na+的翻译后变化， Ca2+通道和NMDA-，AMPA-谷氨酸受体，并引起突触的变化 海马的活性。 AIM＃1：确定TS65DN中的PKA途径活动 与LTP和LTD范式有关的海马。确定表达 磷酸化的Creb。 AIM＃2：TS65DN海马中的PKC活动相关 LTP和LTD范式。确定PKC同工型的表达模式。目的 ＃3：确定电压的表达式和翻译后修饰 依赖性Na+，Ca2+通道和NMDA-，AMPA-谷氨酸受体使用 核片钳记录技术和结合研究。的影响 PKC同工型将在永久性NA+的细胞系中进行测试 通道，Ca2+通道，NMDA和AMPA受体。信号转导 DS遗传模型的损害将确定重要目标 智力降低的治疗。此外，这项研究的结果还将 包括进一步了解PKA和PKC的作用以及电压依赖性 在LTP和 有限公司