EMBRYOLOGIC CONSEQUENCES OF TRISOMY 16 IN MICE

16 三体对小鼠的胚胎学影响

• 批准号: 3317597
• 负责人: Mary L Oster-Granite
• 金额: $ 13.95万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1990-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3317597
• 关键词: Alzheimer's disease; Downs syndrome; autoradiography; central nervous system; developmental genetics; developmental neurobiology; gene expression; genetic manipulation; genetic models; genetic regulation; immunochemistry; karyotype; laboratory mouse; model design /development; neurofibrillary tangles; neurotransmitters; nucleic acid hybridization; radiotracer; somatostatin; tissue mosaicism; trisomy

The long term objective of this research program remains the analysis of the developmental consequences of trisomy 16 (Ts16) in the mouse central nervous system Genetic homology between the distal part of the long arm of mouse chromosome 16 (MMU 16) and that portion of human chromosome 21 (HSA 21) which produces Down Syndrome (DS) when present in triplicate has led to studies of the Ts16 mouse as a mod, system for analyzing the ontogenesis of central nervous system deficits observed in DS. including those associated with Alzheimer's Disease AD). All DS individuals who live into the fourth decade invariably develop the neuropathologic stigmata of AD. The specific aim of this research proposal is to examine the ontogenesis and fatal neurons utilizing the peptide somatostatin (SMST) as their neurotransmitter. SMST exerts profound functional effects on cells throughout the body during development. Its mechanism of action is mediated through alteration of transmembrane signalling systems involving cAMP and cGMP as second messengers. In the CNS, neuron populations expressing SMST have been well defined in normal individuals and appear to be "at risk" in AD, since selective degeneration of both cholinergic and SMST neurons occurs, and SMST immunoreactivity is associated with senile plaques in selected region of the neuraxis. The gene encoding proprosomatostatin (Smst) is located on MMU 16, and regulation of its level of expression appears to be affected by the mutation dwarf (dw), also localized to MMU 16. This mutation is associated with elevated levels of SMST during the development of central and peripheral tissues in homozygous dw mice. The exaggerated levels of SMST that occur in Ts16 mice may contribute the deficits in cholinergic and catecholaminergic development that we have observed in Ts16 mice, and to the deficits in cholinergic and interneuronal function that have observed in murine chimeras composed in part of Ts16 cells. We will use immunocytochemical, in situ hybridization, and ligand autoradiographic procedures to quantify the location and distribution of SMST and its receptor during development sections derived from whole Ts16 and normal littermate fetuses from day 10 through 18 gestation. We will examine the brains of aging Ts16 chimeric mice to determine whether senile plaques and neurofibrillary tangles are present in selected regions the of the neuraxis or whether degenerative structures physically different from plaques a tangles are immunoreactive to SMST.

该研究计划的长期目标仍然是 16 三体（Ts16）的发育后果分析 小鼠中枢神经系统之间的遗传同源性 小鼠 16 号染色体长臂的远端部分 (MMU 16) 和 人类 21 号染色体 (HSA 21) 中产生唐氏体的部分 综合症（DS）当一式三份出现时导致了对 Ts16 小鼠作为模型，用于分析个体发生的系统 DS 中观察到中枢神经系统缺陷。包括那些 与阿尔茨海默氏病（AD）有关。 所有 DS 个人 活到四十岁总是会发展出神经病理学 AD的圣痕。 本研究计划的具体目的是 利用肽检查个体发生和致命神经元 生长抑素（SMST）作为它们的神经递质。 SMST发挥 期间对全身细胞产生深远的功能影响 发展。 其作用机制是通过 涉及 cAMP 和的跨膜信号系统的改变 cGMP 作为第二信使。 在中枢神经系统中，神经元群 表达 SMST 已在正常个体中得到明确定义，并且 似乎在AD中“处于危险之中”，因为两者的选择性退化 胆碱能神经元和 SMST 神经元发生，并且 SMST 免疫反应性 与神经轴选定区域的老年斑有关。 编码原生长抑素 (Smst) 的基因位于 MMU 16， 其表达水平的调节似乎受到影响 由突变 dwarf (dw) 引起，也定位于 MMU 16。 突变与 SMST 水平升高有关 纯合 dw 中枢和外周组织的发育 老鼠。 Ts16 小鼠中出现的 SMST 水平过高可能 造成胆碱能和儿茶酚胺能的缺陷 我们在 Ts16 小鼠中观察到的发育以及缺陷 在胆碱能和中间神经元功能中观察到 鼠嵌合体由部分 Ts16 细胞组成。 我们将使用 免疫细胞化学、原位杂交和配体 放射自显影程序来量化位置和 SMST及其受体在发育阶段的分布 来自整个 Ts16 和第 10 天的正常同窝胎儿 到18妊娠期。 我们将检查老化 Ts16 的大脑 嵌合小鼠以确定是否存在老年斑和 神经原纤维缠结存在于选定的区域 神经轴或退行性结构是否物理上不同 斑块中的缠结对 SMST 具有免疫反应。