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

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 21 三体症 (Ts21) 是 由 21 号染色体的三个拷贝的存在引起，并且是最常见的 智力低下的常见遗传原因。 Ts65Dn 三体小鼠具有 最近被开发出来，仅针对小鼠部分是三体性的 16 号染色体与人类 21 号染色体的片段同源 导致精神发育迟滞和易患阿尔茨海默病 DS。这只老鼠表现出异常行为并且在多种方面受到损害 学习范式。我们证明了长时程增强（LTP）和长时程增强 CA1 区域的术语抑郁 (LTD) 分别减少和增加 Ts65Dn小鼠海马的Ts65Dn小鼠。该提案的目标是 寻找导致LTP和LTD异常的机制。三个具体目标是 建议测试LTP和LTD异常是由于信号变化引起的 由蛋白激酶 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变化 海马体的活动。目标#1：确定 Ts65Dn 中的 PKA 通路活性 海马体与 LTP 和 LTD 范式的关系。确定表达式 磷酸化的CREB。目标#2：Ts65Dn 海马体中的 PKC 活性与 LTP 和 LTD 范例。确定 PKC 同种型的表达模式。目的 #3:确定电压的表达和翻译后修饰 依赖的 Na+、Ca2+ 通道和 NMDA-、AMPA- 谷氨酸受体 有核膜片钳记录技术和结合研究。的影响 PKC 同工型将在永久过度表达 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 遗传模型的损伤将决定重要的目标 精神发育迟滞的治疗。此外，这项研究的成果将 包括进一步了解 PKA 和 PKC 的作用以及电压依赖性 LTP 和 LTP 背后机制中的通道以及 NMDA 和 AMPA 受体 有限公司