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综合症的药物。本研究的目的是探讨绿色茶EGCG（一种已知的信号转导和转录激活因子1（STAT 1）抑制剂）是否可以通过干扰STAT 1信号转导来减轻暴露于IFN-g与HIV-1蛋白gp 120和达特的小鼠的艾滋病样神经元损伤。以促炎细胞因子水平增加为特征的免疫激活状态被广泛认为是导致AIDS痴呆样神经元损伤的重要因素，并且神经元中促炎信号传导的关键调节因子是STAT 1。STAT 1激活参与与脑缺血以及AIDS痴呆相关的神经元损伤/死亡。此外，其“激活剂”IFN-g已被证明在HIV阳性个体的脑脊液和大脑中升高。我们的初步研究结果表明，IFN-g增强gp 120和达特的神经毒性作用。此外，在STAT 1缺陷的神经元中，这种联合损伤引起的AIDS痴呆样神经元损伤在很大程度上减弱。我们和其他人已经表明，在AIDS痴呆和中风模型中，用EGCG处理原代神经元分别减少了STAT 1激活和由此产生的神经元损伤。我们推测，EGCG治疗将减少艾滋病痴呆样神经元损伤通过STAT 1抑制。目的1：建立一种能反映艾滋病痴呆神经元损害的小鼠模型。目的2研究STAT 1在IFN-γ、gp 120和达特诱导的小鼠神经元损伤中的作用。为此，我们将比较侧脑室注射IFN-γ和gp 120或达特后，STAT 1缺陷小鼠和对照小鼠的神经元损伤。我们预计STAT 1缺陷小鼠与对照组相比，艾滋病痴呆样神经元损伤将显着减少。目的3研究EGCG对gp 120或达特诱导的IFN-γ介导的STAT 1激活所致小鼠神经元损伤的抑制作用。在这里，我们还计划描绘最有效的EGCG腹腔注射，通过比较艾滋病痴呆样神经元损伤的预防，治疗，并结合预防/治疗的范例。我们假设，与溶剂处理的小鼠相比，EGCG处理的小鼠将显示出艾滋病痴呆样神经元损伤的显着减少。这些数据应该为不久的将来进行人体试验的进一步研究奠定基础。叙述：该项目的目的是研究绿色茶提取的EGCG是否可以减轻小鼠模型中的艾滋病样神经元损伤。我们假设，与溶剂处理的小鼠相比，EGCG处理的小鼠将显示出艾滋病痴呆样神经元损伤的显着减少。这些数据应该为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.