ESTRADIOL INTERACTIONS WITH THE PROTEASOME IN HIV REGULATION

雌二醇与蛋白酶体在 HIV 调节中的相互作用

• 批准号: 7720439
• 负责人: ANNADORA J BRUCE-KELLER
• 金额: $ 24万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720439
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Age; Attenuated; Cause of Death; Clinical; Computer Retrieval of Information on Scientific Projects Database; Data; Disease; Disease Progression; Estradiol; Estrogens; Female; Funding; Genetic Transcription; Goals; Gonadal Steroid Hormones; Grant; HIV; HIV Infections; HIV-1; Hormones; Human; Incidence; Infection; Institution; Lead; Lipodystrophy; Maintenance; Molecular; Physiology; Play; Pregnancy; Proteins; Proteomics; Regulation; Research; Research Personnel; Resources; Role; Serum; Source; Staging; Syndrome; Testing; United States National Institutes of Health; Viral; Viral Load result; Woman; Women' s Role; design; men; multicatalytic endopeptidase complex; novel; promoter; tool

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall goal of this proposal is to test the hypothesis that estrogen can decrease HIV viral load by decreasing viral replication. As AIDS is now the third leading cause of death among women ages 25-44, understanding the role that female sex hormones might play in the physiology of HIV-1 infection is especially critical. Many manifestations of HIV differ in women, including that women generally have lower HIV viral loads compared to men at similar stages of disease, and have attenuated or absent disease progression during pregnancy. Conversely, while studies suggest that women may be more vulnerable to certain AIDS-related illnesses, such as HIV dementia and lipodystrophy, there is data strongly suggesting that an estrogen deficient state can be associated with HIV infection. Evaluated as a whole, this clinical evidence indicates that female hormones such as estrogen could act to maintain low viral titers, and suggest that maintenance of serum estradiol levels could decrease the incidence of AIDS-related syndromes. While the mechanisms whereby estrogen modulates HIV infection are still very poorly understood, data from our labs show that estrogen attenuates Tat-induceed transcription at the long-term repeat (LTR) domain of the HIV-1 promoter. These studies are thus designed to use novel molecular, pharmacological, and proteomic tools to determine the mechanisms whereby estrogen modulates HIV replication, with specific emphasis on the role of the multicatalytic proteasome as a convergence point for estrogen and Tat in HIV regulation. The specific aims are to 1: To test the hypothesis that estrogen has specific negative effects on Tat-induced LTR activation; 2: To test the hypothesis that the effects of estrogen on the HIV-1 LTR are proteasome dependent; and 3: To determine the full proteomic mechanisms whereby estrogen modulates the HIV-1 LTR. Realization of these goals could lead to identification of novel and pertinent protein regulators of HIV-1 replication, the manipulation of which might allow for more precise control over HIV infection in humans.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该提案的总体目标是检验以下假设：雌激素可以通过减少病毒复制来降低HIV病毒载量。 由于艾滋病现在是25-44岁妇女中第三大死亡原因，因此了解女性性激素在HIV-1感染生理学中可能起的作用尤其重要。 艾滋病毒的许多表现在女性中有所不同，包括与疾病相似的男性相比，女性通常具有较低的艾滋病毒病毒负荷，并且在怀孕期间衰减或没有疾病的进展。 相反，尽管研究表明，女性可能更容易受到某些与艾滋病相关疾病的攻击，例如HIV痴呆和脂肪营养不良，但有强烈的数据表明，雌激素缺乏状态可能与HIV感染有关。 总体评估，该临床证据表明，雌激素等雌激素可以起作用以维持低病毒滴度，并表明维持血清雌二醇水平可以降低与艾滋病相关综合征的发生率。 虽然雌激素调节HIV感染的机制仍然非常了解，但我们实验室的数据表明，在HIV-1启动子的长期重复（LTR）结构域中，雌激素减弱了TAT诱导的转录。 因此，这些研究旨在使用新型分子，药理和蛋白质组学工具来确定雌激素调节HIV复制的机制，并特别强调多催化蛋白酶体作为雌激素和TAT在HIV调节中的收敛点。 具体目的是1：检验雌激素对TAT诱导的LTR激活具有特定的负面影响的假设； 2：检验雌激素对HIV-1 LTR的影响的假设是蛋白酶体的；和3：确定雌激素调节HIV-1 LTR的完整蛋白质组学机制。 实现这些目标可能会导致对HIV-1复制的新型和相关蛋白质调节剂的识别，其操纵可能允许对人类的HIV感染进行更精确的控制。