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Green tea derived EGCG opposes AIDS dementia-like neuronal damage

绿茶提取的 EGCG 可以对抗艾滋病痴呆样神经元损伤

基本信息

批准号：
7460708
负责人：
Jun Tan
金额：
$ 18.38万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-05 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7460708
关键词：
AIDS Dementia Complex Attenuated Bax protein Biochemical Biological Assay Brain Brain Ischemia C57BL/6 Mouse Cells Cerebrospinal Fluid Cessation of life Data Development Disruption Dose Exhibits Foundations Future Glycoproteins Goals Green tea HIV Envelope Protein gp120 HIV Seropositivity HIV Transactivator Protein HIV-1 Human Image Analysis Immune In Vitro Individual Inflammatory Injection of therapeutic agent Interferon Type II Interferons Intraperitoneal Injections Ischemia Lactate Dehydrogenase Lead Mediating Modeling Mus Neurodegenerative Disorders Neuroglia Neuronal Injury Neurons Pathology Phosphorylation Phosphotransferases Pilot Projects Principal Investigator Proteins Purpose Research Resistance Role STAT1 protein Signal Pathway Signal Transduction Signaling Molecule Staining method Stains Stroke Testing Therapeutic Therapeutic Effect Transcriptional Activation Transducers Viral Work cell injury cytokine day desire dosage gallocatechol in vivo inhibitor/antagonist mouse model neuropathology neurotoxic neurotoxicity prevent programs prophylactic

项目摘要

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.

描述(申请人提供)：我们的长期目标是开发有效的治疗艾滋病痴呆症的药物。本项目的目的是研究绿茶EGCG，一种已知的信号转导和转录激活1(STAT1)的抑制剂，是否可以通过干扰信号转导和转录激活1(STAT1)信号来减轻暴露于带有HIV-1蛋白gp120和TAT的干扰素-g的小鼠的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的激活参与了与脑缺血和艾滋病痴呆相关的神经元损伤/死亡。此外，它的“激活物”干扰素-g已被证明在艾滋病毒阳性者的脑脊液和大脑中都升高。我们的初步研究结果表明，干扰素-g增强了gp120和Tat的神经毒性作用。此外，在STAT1缺乏的神经元中，这种联合侮辱造成的艾滋病痴呆样神经元损伤在很大程度上得到了减轻。我们和其他人已经证明，在艾滋病痴呆和中风模型中，EGCG治疗初级神经元分别减少了STAT1的激活和由此导致的神经元损伤。我们假设EGCG治疗将通过抑制STAT1减少艾滋病痴呆样神经元损伤。目的1是建立一个代表艾滋病痴呆可能表现出的神经元损伤的小鼠模型。目的2研究STAT1在干扰素-g、gp120和TAT诱导的小鼠神经元损伤中的作用。为此，我们将比较STAT1缺陷小鼠和对照组小鼠在脑室注射干扰素-g与gp120或Tat后的神经元损伤。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着减少。目的研究EGCG对gp120或Tat诱导的干扰素-g介导的STAT1激活所致的小鼠神经元损伤的抑制作用。在这里，我们还计划通过比较预防、治疗和联合预防/治疗方案中的艾滋病痴呆样神经元损伤来描述最有效的EGCG腹腔注射。我们假设，与赋形剂治疗的小鼠相比，EGCG治疗的小鼠将显着减少艾滋病痴呆样神经元损伤。这些数据应该会为在不久的将来进行人体试验的进一步研究奠定基础。说明：该项目的目的是调查绿茶提取的EGCG是否可以减轻小鼠模型中艾滋病样神经元的损伤。我们假设，与赋形剂治疗的小鼠相比，EGCG治疗的小鼠将显着减少艾滋病痴呆样神经元损伤。这些数据应该会为在不久的将来进行人体试验的进一步研究奠定基础。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Psychiatric implications of hepatitis-C infection.

丙型肝炎感染的精神影响。

DOI：
10.1615/critrevneurobiol.v19.i2-3.20
发表时间：
2007
期刊：
Critical reviews in neurobiology
影响因子：
0
作者：
Giunta,Brian;Somboonwit,Charurut;Nikolic,WilliamV;Rrapo,Elona;Tan,Jun;Shapshak,Paul;Fernandez,Francisco
通讯作者：
Fernandez,Francisco

Antiretroviral medications disrupt microglial phagocytosis of β-amyloid and increase its production by neurons: implications for HIV-associated neurocognitive disorders.