Modulation of Sp1/Sp3 by HIV-1 Tat Contributes to oxidative stress in HIV-PAH
HIV-1 Tat 对 Sp1/Sp3 的调节有助于 HIV-PAH 的氧化应激
基本信息
- 批准号:8992878
- 负责人:
- 金额:$ 46.03万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-07-17 至 2019-04-30
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Since the introduction of the highly active antiretroviral combinatorial therapies for HIV (HAART) the pathogenesis of HIV infection is now more commonly a chronic, long-term infection that has dramatically changed the epidemiology of this disease. Long-term exposure to low levels of viral replication has unmasked susceptibilities to a number of cardiac and pulmonary diseases that are now more common causes of morbidity and mortality. For example, HIV-associated pulmonary arterial hypertension (HIV-PAH) PAH is approximately 25 times more prevalent among HIV infected individuals than in the general population. We have found that the HIV Tat protein promotes a number of pro-oxidative and pro-inflammatory responses that are not directly related to its function as a viral transcriptional regulator. For example, we and others have demonstrated that Tat induces oxidative stress via depletion of glutathione and alteration of manganese- dependent superoxide dismutase (MnSOD). In endothelial cells, the resultant increase in oxidants can promote a number of physiological responses such as inflammation, apoptosis and subsequent proliferation of apoptosis-resistant cells that can contribute to the occlusion of pulmonary vessels. Thus, we propose that Tat- induced oxidative stress has a central role in initiating the pathogenic cascade that ultimate leads to pulmonary vascular remodeling in HIV-PAH. In this application, we seek to examine the mechanisms whereby the HIV-1 Tat protein modulates sod2 expression thereby contributing to a state of oxidative stress. We have defined a Tat-sensitive Sp-responsive element (TSS) containing multiple binding sites for the oxidant sensitive Sp family of transcription factors in the regions of the sod2 promoter proximal (up to nucleotide -210) to the transcriptional start and have shown that Tat decreases the Sp1/Sp3 ratio on the TSS. Given that Sp3 has reduced transcriptional activity compared to Sp1 and an inhibitory domain that that represses transcription, this shift in occupancy of the promoter will result in alteration of sod2 transcription. Our hypothesis is that HIV-1 Tat dysregulates sod2 expression via modulation of Sp1 and Sp3 transcription factors and contributes to a state of oxidative stress during HIV infection. In order to address the hypothesis we have crafted a research plan that combines in vivo mouse models to examine the oxidative state in the lungs during HIV infection and in vitro mechanistic experiments to probe potential molecular mechanisms for how Tat alters the Sp1/Sp3 ratio on the sod2 promoter. Lastly we will leverage our current bank of bronchalveolar lavage (BAL) and blood biospecimens from HIV+ individuals with and without PAH to address whether in HIV-infected patients, to investigate oxidative stress in human biological specimens of HIV-PAH and to ask mechanistic questions regarding the modulation of sod2 in HIV infection.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据
数据更新时间:2024-06-01
ADELA COTA-GOMEZ的其他基金
GEMS, a Short-Term Summer Internship Program for Diverse Students
GEMS,针对多元化学生的短期暑期实习计划
- 批准号:1002341710023417
- 财政年份:2010
- 资助金额:$ 46.03万$ 46.03万
- 项目类别:
GEMS, a Short-Term Summer Internship Program for Diverse Students
GEMS,针对多元化学生的短期暑期实习计划
- 批准号:1016689810166898
- 财政年份:2010
- 资助金额:$ 46.03万$ 46.03万
- 项目类别:
Role of RelB in HIV-1 Tat-mediated immune responses
RelB 在 HIV-1 Tat 介导的免疫反应中的作用
- 批准号:70812437081243
- 财政年份:2002
- 资助金额:$ 46.03万$ 46.03万
- 项目类别:
Role of RelB in HIV-1 Tat-mediated immune responses
RelB 在 HIV-1 Tat 介导的免疫反应中的作用
- 批准号:69148426914842
- 财政年份:2002
- 资助金额:$ 46.03万$ 46.03万
- 项目类别:
Role of RelB in HIV-1 Tat-mediated immune responses
RelB 在 HIV-1 Tat 介导的免疫反应中的作用
- 批准号:64916836491683
- 财政年份:2002
- 资助金额:$ 46.03万$ 46.03万
- 项目类别:
Role of RelB in HIV-1 Tat-mediated immune responses
RelB 在 HIV-1 Tat 介导的免疫反应中的作用
- 批准号:66277196627719
- 财政年份:2002
- 资助金额:$ 46.03万$ 46.03万
- 项目类别:
Role of RelB in HIV-1 Tat-mediated immune responses
RelB 在 HIV-1 Tat 介导的免疫反应中的作用
- 批准号:67717506771750
- 财政年份:2002
- 资助金额:$ 46.03万$ 46.03万
- 项目类别:
相似国自然基金
仙茅酚苷类成分靶向组蛋白去乙酰化酶HDAC1抑制BMSC衰老防治老年性骨质疏松的机制
- 批准号:82304806
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
丁酸上调HSD11b2乙酰化抑制HPA轴激活改善孤独症样社交障碍机制研究
- 批准号:82372559
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:面上项目
ACSS2介导的乙酰辅酶a合成在巨噬细胞组蛋白乙酰化及急性肺损伤发病中的作用机制研究
- 批准号:82370084
- 批准年份:2023
- 资助金额:48 万元
- 项目类别:面上项目
高糖水平通过JUN乙酰化修饰上调NCAPD3促进结直肠癌发生的分子机制
- 批准号:82303250
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
芪苓温肾消囊颗粒通过HDAC5调控GATA1启动子区H3K27乙酰化改善PCOS妊娠早期流产的机制研究
- 批准号:82374498
- 批准年份:2023
- 资助金额:48 万元
- 项目类别:面上项目
相似海外基金
Role of the ER acetyl CoA transporter in alcoholic pancreatitis
ER 乙酰 CoA 转运蛋白在酒精性胰腺炎中的作用
- 批准号:1035859110358591
- 财政年份:2021
- 资助金额:$ 46.03万$ 46.03万
- 项目类别:
Using NAD+ precursor for treatment of global cerebral ischemia
利用NAD前体治疗全脑缺血
- 批准号:1029466110294661
- 财政年份:2021
- 资助金额:$ 46.03万$ 46.03万
- 项目类别:
Using NAD+ precursor for treatment of global cerebral ischemia
利用NAD前体治疗全脑缺血
- 批准号:1043988710439887
- 财政年份:2021
- 资助金额:$ 46.03万$ 46.03万
- 项目类别:
Enhancer activation mechanisms in cranial neural crest osteoblast differentiation
颅神经嵴成骨细胞分化的增强子激活机制
- 批准号:1047530810475308
- 财政年份:2021
- 资助金额:$ 46.03万$ 46.03万
- 项目类别:
Enhancer activation mechanisms in cranial neural crest osteoblast differentiation
颅神经嵴成骨细胞分化的增强子激活机制
- 批准号:1066398510663985
- 财政年份:2021
- 资助金额:$ 46.03万$ 46.03万
- 项目类别: