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

唐氏综合征（DS）或21三体是最常见的遗传原因的精神发育迟滞。它发生在约1/800至1/1000活产。精神发育迟滞和中年阿尔茨海默病（AD）的发展是DS神经病理学的标志。以前的研究表明，DS神经元在培养中表现出升高的细胞内自由基和脂质过氧化，导致增加神经元死亡。这种氧化应激和神经退行性变的增加可能有助于DS患者的精神发育迟滞和AD的发展。我们的研究目标是表征参与神经元氧化应激和退行性变的分子机制。本项目将研究Ets-2和Cu/Zn超氧化物歧化酶（SOD-1）过表达在DS神经变性中的作用。以下假设将被测试：1。DS神经元中转录因子Ets-2的过度表达通过改变控制神经元存活和死亡的基因的表达而损害神经元的活力。更具体地，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）活性的增加可能有助于氧化应激和DS神经元变性。研究将侧重于：1）Ets-2和SOD-1在培养的DS和Ets-2转基因神经元中的功能分析; 2）Ets- 2和SOD-1与DS和AD患者以及Ets-2转基因小鼠脑中神经退行性改变的关联。具体目标是：一曰：以确定Ets-2过表达在培养物中以及DS和AD患者的脑中的DS神经元变性中的作用。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神经元变性中的作用。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会确定新的分子靶点，用于设计神经保护疗法，用于治疗DS患者的精神发育迟滞和预防AD。

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.