Green tea derived EGCG opposes AIDS dementia-like neuronal damage

描述（由申请人提供）：我们的长期目标是开发有效的艾滋病痴呆复合物药物。该项目的目的是研究绿茶EGCG（一种已知的信号传感器和转录激活1 （STAT1）抑制剂）是否可以通过破坏带有HIV-1蛋白gp120和Tat的IFN-g小鼠的STAT1信号通路来减轻艾滋病样神经元损伤。以促炎细胞因子水平升高为特征的免疫激活状态被广泛认为是导致艾滋病痴呆样神经元损伤的重要因素，而神经元中促炎信号的关键调节因子是STAT1。STAT1激活参与脑缺血相关的神经元损伤/死亡，以及艾滋病痴呆。此外，它的“激活剂”IFN-g已被证明在艾滋病毒阳性个体的脑脊液和大脑中都有升高。我们的初步研究结果表明，IFN-g增强了gp120和Tat的神经毒性作用。此外，在STAT1缺失的神经元中，这种联合损伤导致的艾滋病痴呆样神经元损伤在很大程度上减弱。我们和其他人已经证明，用EGCG治疗原代神经元分别减少了艾滋病痴呆和中风模型中STAT1的激活和由此产生的神经元损伤。我们假设EGCG治疗可以通过抑制STAT1减少艾滋病痴呆样神经元损伤。目的1是建立一个小鼠模型，代表艾滋病痴呆中可能出现的神经元损伤。目的2将描述STAT1在IFN-g、gp120和Tat诱导的小鼠神经损伤中的作用。为此，我们将比较在脑室内注射IFN-g与gp120或Tat后，STAT1缺陷小鼠与对照组小鼠的神经元损伤情况。我们预计，与对照组相比，STAT1缺陷小鼠的艾滋病痴呆样神经元损伤将显著减少。目的3将研究EGCG在gp120或Tat存在下对IFN-g介导的STAT1激活引起的神经元损伤的抑制作用。在这里，我们还计划通过比较预防、治疗和预防/治疗联合模式对艾滋病痴呆样神经元损伤的影响，来描述最有效的EGCG腹腔注射。我们假设，egcg处理的小鼠在艾滋病痴呆样神经元损伤方面将显著减少，与药物处理的小鼠相比。这些数据应该为在不久的将来进行人体试验的进一步研究奠定基础。本项目的目的是研究绿茶衍生的EGCG是否可以减轻小鼠模型中艾滋病样神经元损伤。我们假设，egcg处理的小鼠在艾滋病痴呆样神经元损伤方面将显著减少，与药物处理的小鼠相比。这些数据应该为在不久的将来进行人体试验的进一步研究奠定基础。

DESCRIPTION (provided by applicant): Our long term goal is to develop effective agents for AIDS dementia complex. The purpose of this project is to investigate if green tea EGCG, a known inhibitor of signal transducer and activation of transcription 1 (STAT1), could attenuate AIDS-like neuronal damage through disruption STAT1 signaling in mice exposed to IFN-g with HIV-1 proteins gp120 and Tat. A state of immune activation characterized by increased levels of pro-inflammatory cytokines is widely regarded as an important factor leading to AIDS dementia-like neuronal damage and a key regulator for pro-inflammatory signaling in neurons is STAT1. STAT1 activation is involved in neuronal injury/death associated with brain ischemia, as well as AIDS dementia. Moreover its "activator" IFN-g, has been shown to be elevated both in the cerebrospinal fluid and brains of HIV positive individuals. Results from our pilot studies suggest that IFN-g enhances the neurotoxic effects of gp120 and Tat. Further, AIDS dementia-like neuronal damage from this combined insult was largely attenuated in STAT1 deficient neurons. We and others have shown that the treatment of primary neurons with EGCG reduces STAT1 activation and resultant neuronal injury in models of AIDS dementia and stroke, respectively. We hypothesize that EGCG treatment will decrease AIDS dementia-like neuronal damage via STAT1 suppression. Aim 1 is to establish a mouse model representative of the possible neuronal damage exhibited in AIDS dementia. Aim 2 will characterize the role of STAT1 in mediating neuronal injury induced by IFN-g and gp120 and Tat in mice. To this end we will compare the neuronal damage in STAT1 deficient mice to control mice after intracerebroventricular injection of IFN-g with gp120 or Tat. We expect STAT1 deficient mice will show a marked decrease in AIDS dementia-like neuronal damage compared to control. Aim 3 will investigate the effects of EGCG on inhibition of the neuronal damage resulting from IFN-g mediated STAT1 activation in the presence of gp120 or Tat in mice. Here we also plan to delineate the most effective EGCG intraperitoneal injection by comparing AIDS dementia-like neuronal damage in prophylactic, therapeutic, and combined prophylactic/therapeutic paradigms. We hypothesize that EGCG-treated mice will show significant decreases in AIDS dementia-like neuronal damage when compared to vehicle-treated mice. These data should lay the foundation for further research leading to human trials in the near future. Narrative: The purpose of this project is to investigate if green tea derived EGCG could attenuate AIDS-like neuronal damage in the mouse model. We hypothesize that EGCG-treated mice will show significant decreases in AIDS dementia-like neuronal damage when compared to vehicle-treated mice. These data should lay the foundation for further research leading to human trials in the near future.