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

唐氏综合征(DS)或21三体是导致智力低下的最常见的遗传原因。它发生在大约每800名活产婴儿中就有1名到每1000名活产婴儿中有1名。智力低下和中年后发展为阿尔茨海默病(AD)是DS神经病理学的特征。以往的研究表明，培养的DS神经元表现出细胞内自由基和脂质过氧化增加，导致神经元死亡增加。这种氧化应激和神经变性的增加可能是DS患者智力低下和AD发展的原因之一。本研究的目的是研究DS患者神经元氧化应激和变性的分子机制。本项目将研究Ets-2和铜/锌超氧化物歧化酶(SOD-1)过表达在DS神经退行性变中的作用。将检验以下假设：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生存能力。更具体地说，将测试ETS-2下调Bcl-2和上调Bax和P53蛋白水平的可能性。2.铜锌超氧化物歧化酶(SOD-1)活性升高可能参与氧化应激和DS神经元变性。本研究将集中于：1)培养的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患者及Ets-2转基因小鼠脑内神经退行性改变的关系。本研究的具体目的是：1：探讨Ets-2过度表达在DS神经元变性中的作用，以及在DS和AD患者脑中的作用。2：研究Ets-2在正常神经元发育过程中的作用。3：探讨SOD-1在DS神经元退行性变中的作用。这些实验将为了解DS和AD中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，这项研究的结果可能为设计治疗智力低下和预防DS患者阿尔茨海默病的神经保护疗法确定新的分子靶点。

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.