ROLE OF ETS-2 AND SOD-1 IN DOWN SYNDROME NEUROPATHOLOGY

ETS-2 和 SOD-1 在唐氏综合症神经病理学中的作用

• 批准号: 6637056
• 负责人: JORGE A BUSCIGLIO
• 金额: $ 3.94万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6637056
• 关键词: Bax gene /protein; Downs syndrome; developmental neurobiology; embryo /fetus tissue /cell culture; enzyme activity; genetically modified animals; human fetus tissue; human tissue; laboratory mouse; neural degeneration; neuropathology; oxidative stress; p53 gene /protein; superoxide dismutase; transcription factor

Down's syndrome (DS) or trisomy 21 is the most frequent genetic cause of mental retardation. It occurs in about 1 in 800 to 1 in 1000 live births. Mental retardation and development of Alzheimer's disease (AD) by middle age are hallmarks of DS neuropathology. Previous studies demonstrated that DS neurons in culture exhibit elevated intracellular free radicals and lipid peroxidation leading to increased neuronal death. This increase in oxidative stress and neurodegeneration may contribute to mental retardation and the development of AD in DS patient. The goal of our research is to characterize the molecular mechanisms involved in neuronal oxidative stress and degeneration in DS. This project will study the role of Ets-2 and Cu/Zn superoxide dismutase (SOD-1) over- expression in DS neurodegeneration. The following hypotheses will be tested: 1. Over-expression of the transcription factor Ets-2 in DS neurons compromises neuronal viability by altering the expression of genes that control neuronal survival and death. More specifically, the possibility that Ets-2 down-regulates Bcl-2 and up-regulates Bax and p53 protein levels will be tested. 2. Increased activity of Cu/Zn superoxide dismutase (SOD- 1) may contribute to oxidative stress and DS neuronal degeneration. The research will focus on: 1) the functional analysis of Ets-2 and SOD-1 in DS and Ets-2 transgenic neurons in culture; and 2) the association of Ets- 2 and SOD-1 with neurodegenerative changes in the brains of DS and AD patients and Ets-2 transgenic mice. The specific aims are: 1: to determine the role of Ets-2 over-expression in DS neuronal degeneration in culture and in the brains of DS and AD patients. 2: To characterize the role of Ets-2 during normal neuronal development. 3: To determine the role of SOD-1 in DS neuronal degeneration. These experiments will provide valuable information towards understanding the molecular basis of neuronal dysfunction and death in DS and AD. In addition, the results of this investigation may identify new molecular targets for the design of neuroprotective therapies for the treatment of mental retardation and the prevention of AD in DS patients.

Down的综合征（DS）或三体疾病是智力低下的最常见遗传原因。它发生在800至1000分之一的活产中。到中年，阿尔茨海默氏病（AD）的智力低下和发展是DS神经病理学的标志。先前的研究表明，培养中的DS神经元表现出升高的细胞内自由基和脂质过氧化，从而导致神经元死亡增加。 DS患者中氧化应激和神经退行性变化的增加可能导致智力低下和AD的发展。我们研究的目的是表征与DS中神经元氧化应激和变性有关的分子机制。该项目将研究DS神经变性中ETS-2和Cu/Zn超氧化物歧化酶（SOD-1）过度表达的作用。将测试以下假设：1。DS神经元中转录因子-2的过表达，通过改变控制神经元存活和死亡的基因的表达来损害神经元的生存力。更具体地说，将测试ETS-2下调BCL-2并上调BAX和p53蛋白水平的可能性。 2。Cu/Zn超氧化物歧化酶（SOD-1）的活性增加可能导致氧化应激和DS神经元变性。该研究将重点放在：1）培养中DS和ETS-2转基因神经元中ETS-2和SOD-1的功能分析； 2）ETS-2和SOD-1与DS和AD患者的大脑以及ETS-2转基因小鼠的神经退行性变化的关联。具体目的是：1：确定ETS-2过表达在DS神经元变性中在培养和DS和AD患者的大脑中的作用。 2：表征ETS-2在正常神经元发育中的作用。 3：确定SOD-1在DS神经元变性中的作用。这些实验将提供有价值的信息，以了解DS和AD中神经元功能障碍和死亡的分子基础。此外，这项研究的结果可以确定用于设计神经保护疗法的新分子靶标，以治疗智力低下和预防DS患者的AD。