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

唐氏综合症（DS）或21三体是最常见的智力迟钝的遗传原因。它大约发生在800到1000个活产儿中。智力发育迟滞和老年痴呆症（AD）发展到中年是退行性痴呆神经病理学的标志。先前的研究表明，培养的DS神经元表现出细胞内自由基升高和脂质过氧化，导致神经元死亡增加。这种氧化应激和神经退行性变的增加可能导致退行性椎体滑移患者的智力迟钝和AD的发展。我们的研究目的是表征神经元氧化应激和退行性痴呆的分子机制。本项目将研究Ets-2和Cu/Zn超氧化物歧化酶（SOD-1）过表达在退行性椎体滑移神经退行性变中的作用。以下假设将被检验：1。转录因子Ets-2在DS神经元中的过度表达通过改变控制神经元生存和死亡的基因的表达而损害神经元的活力。更具体地说，Ets-2下调Bcl-2和上调Bax和p53蛋白水平的可能性将被测试。2. Cu/Zn超氧化物歧化酶（SOD- 1）活性升高可能与氧化应激和DS神经元变性有关。主要研究方向为：1)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与退行性痴呆患者和Ets-2转基因小鼠大脑神经退行性改变的关系。具体目的是：1 .确定Ets-2过表达在DS和AD患者培养和大脑中DS神经元变性中的作用。2：表征Ets-2在正常神经元发育中的作用。3：探讨SOD-1在退行性椎体变性中的作用。这些实验将为了解退行性椎体滑移和阿尔茨海默病神经元功能障碍和死亡的分子基础提供有价值的信息。此外，本研究结果可能为设计治疗智力迟钝和预防退行性椎体滑移患者AD的神经保护疗法提供新的分子靶点。

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.