Impact of Opiate abuse on HIV-mediated Pulmonary Vascular Remodeling
阿片类药物滥用对 HIV 介导的肺血管重塑的影响
基本信息
- 批准号:9115350
- 负责人:
- 金额:$ 48.86万
- 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:2015-09-01 至 2016-08-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAcquired Immunodeficiency SyndromeAdultAntioxidantsApoptosisApoptoticArterial DisorderAutophagocytosisBasic ScienceBiological ModelsBlood VesselsCardiopulmonaryCellsChildCocaineComplexDataDevelopmentDiagnosisDiseaseDrug abuseEndothelial CellsExcisionExposure toGenerationsGenesGenetic TranscriptionGoalsHIVHIV InfectionsHIV-1HealthHeartHematological DiseaseHeroinHumanHypertrophyIllicit DrugsImmunologic Deficiency SyndromesIn VitroIncidenceIndividualInterventionInvestigationLesionLesion by StageLinkLungMacacaMedialMediatingMitochondriaMorbidity - disease rateMorphineOpioidOrganellesOxidative StressPathogenesisPatientsPilot ProjectsPrevalenceProliferatingProteinsPublishingPulmonary vesselsRattusReactive Oxygen SpeciesResearchResistanceRisk FactorsRoleSIVSignal PathwaySourceSpecimenStagingStructure of parenchyma of lungTestingTherapeutic InterventionTrans-ActivatorsTransgenic OrganismsUnited StatesVascular DiseasesVascular Endothelial CellVascular remodelingViralViral ProteinsVirusWorkabstractingantiretroviral therapyarteriolebasecytotoxicdrug of abuseendothelial dysfunctionimprovedin vivoinhibitor/antagonistinnovationintravenous drug useintravenous drug usermortalitynon-drugnovelnovel therapeuticsopioid abusepreventpulmonary arterial hypertensionresearch studyvascular bed
项目摘要
DESCRIPTION (provided by applicant):
Improved survival among human immuno-deficiency virus (HIV-1) infected individuals with the advent of antiretroviral therapy has clearly led to serious increase in the prevalence of noninfectious complications. In this regard, one of the most devastating sequelae is the development of pulmonary arterial hypertension in HIV-infected individuals (HPAH). Intravenous drug use (IVDU) accounts for one-third of all new cases of AIDS in the United States and has been identified as the most common risk factor in the individuals diagnosed with HPAH. Our recent findings showing enhanced pulmonary vascular remodeling in HIV-infected lung tissues from IV heroin and/or cocaine abusers and in simian immunodeficiency (SIV) -infected macaques exposed to morphine indicate that illicit drugs and HIV-1 potentially act in concert to cause pulmonary arteriopathy. Furthermore, SIV-infected morphine treated macaques were found to have increased number of apoptotic endothelial cells in the early stage lesions, whereas complete occlusion by actively proliferating endothelial simian immunodeficiency (SIV) cells was observed in the advanced stage plexiform lesions. This observation was further supported by our in- vitro findings showing enhanced apoptosis followed by significantly increased proliferation of human pulmonary endothelial cells on simultaneous treatment with HIV- transactivator of transcription (Tat) protein and morphine compared to either treatment alone. Based on our recent preliminary findings, the hypothesis of our pilot study is that the combined exposure of pulmonary endothelial cells to HIV-protein(s) and morphine results in the induction of autophagy that leads to enhanced proliferation of endothelial cells and severe pulmonary vascular remodeling. This hypothesis will be tested by pursuing three specific aims. In the first aim we will evaluate the effect of HIV-Tat and morphine on the oxidative stress mediated bulk autophagy in endothelial cells. In the second aim, we propose to delineate the role of selective autophagy in Tat and morphine mediated enhanced proliferation. Third aim will be focused on in-vivo investigation of PAH and autophagy in HIV-1 Tg rats with or without morphine exposure. In addition, ex-vivo investigation of autophagy using lung specimens from HIV- infected IVDUs and SIV-infected morphine exposed macaques will be tested. These studies are innovative because to the best of our knowledge it will be the first attempt to understand the potential link between the role of autophagy in the morphine and HIV-proteins mediated apoptosis resistant enhanced proliferation. The proposed research will enhance our understanding of the fundamental mechanisms involved in the pathogenesis of HPAH and therefore is directly responsive to RFA-HL-14-024 (Basic Research in the Pathogenesis of HIV-Related Heart, Lung, and Blood (HLB) Diseases in Adults and Children).
描述(由申请人提供):
随着抗逆转录病毒疗法的出现,人类免疫缺陷病毒(HIV-1)感染者的存活率有所提高,这显然导致非感染性并发症的发病率严重增加。在这方面,最具破坏性的后遗症之一是艾滋病毒感染者肺动脉高压(HPAH)的发展。静脉注射毒品(IVDU)占美国所有艾滋病新发病例的三分之一,并已被确定为HPAH患者最常见的危险因素。我们最近的研究结果显示,增强肺血管重塑艾滋病毒感染的肺组织从静脉注射海洛因和/或可卡因滥用者和猴免疫缺陷(SIV)感染的猕猴暴露于吗啡表明,非法药物和HIV-1可能共同作用,导致肺动脉病。此外,SIV感染的吗啡治疗的猕猴被发现有增加的凋亡内皮细胞在早期病变,而完全闭塞的积极增殖的内皮猿免疫缺陷(SIV)细胞观察到在晚期丛状病变。我们的体外发现进一步支持了这一观察结果,显示与单独处理相比,用HIV-转录反式激活因子(达特)蛋白和吗啡同时处理后,人肺内皮细胞的凋亡增强,随后增殖显著增加.基于我们最近的初步发现,我们的初步研究的假设是,肺内皮细胞暴露于HIV蛋白和吗啡的组合导致诱导自噬,从而导致内皮细胞增殖增强和严重的肺血管重塑。这一假设将通过追求三个具体目标来检验。在第一个目标中,我们将评估HIV-Tat和吗啡对内皮细胞中氧化应激介导的大量自噬的影响。在第二个目标中,我们建议描绘选择性自噬在达特和吗啡介导的增殖增强中的作用。第三个目标将集中在体内研究PAH和自噬在HIV-1转基因大鼠有或没有吗啡暴露。此外,将测试使用来自HIV感染的IVDU和SIV感染的暴露于吗啡的猕猴的肺标本的自噬的离体研究。这些研究是创新的,因为据我们所知,这将是第一次尝试了解自噬在吗啡和HIV蛋白介导的抗凋亡增强增殖中的作用之间的潜在联系。拟议的研究将提高我们对HPAH发病机制中涉及的基本机制的理解,因此直接响应RFA-HL-14-024(成人和儿童HIV相关心脏、肺和血液(HLB)疾病发病机制的基础研究)。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Navneet Kaur Dhillon其他文献
Navneet Kaur Dhillon的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Navneet Kaur Dhillon', 18)}}的其他基金
Drug abuse and HIV-associated pulmonary vascular injury
药物滥用和 HIV 相关肺血管损伤
- 批准号:
10330405 - 财政年份:2021
- 资助金额:
$ 48.86万 - 项目类别:
Drug abuse and HIV-associated pulmonary vascular injury
药物滥用和 HIV 相关肺血管损伤
- 批准号:
10799336 - 财政年份:2021
- 资助金额:
$ 48.86万 - 项目类别:
Drug abuse and HIV-associated pulmonary vascular injury
药物滥用和 HIV 相关肺血管损伤
- 批准号:
10161471 - 财政年份:2021
- 资助金额:
$ 48.86万 - 项目类别:
Drug abuse and HIV-associated pulmonary vascular injury
药物滥用和 HIV 相关肺血管损伤
- 批准号:
10539306 - 财政年份:2021
- 资助金额:
$ 48.86万 - 项目类别:
Impact of Opiate abuse on HIV-mediated Pulmonary Vascular Remodeling
阿片类药物滥用对 HIV 介导的肺血管重塑的影响
- 批准号:
9204520 - 财政年份:2016
- 资助金额:
$ 48.86万 - 项目类别:
Extracellular Vesicles and and HIV/cocaine associated cardiopulmonary dysfunction
细胞外囊泡和 HIV/可卡因相关的心肺功能障碍
- 批准号:
9204218 - 财政年份:2016
- 资助金额:
$ 48.86万 - 项目类别:
HIV/Cocaine mediated human pulmonary vascular remodeling: Role of BMPR signaling.
HIV/可卡因介导的人肺血管重塑:BMPR 信号传导的作用。
- 批准号:
8508237 - 财政年份:2012
- 资助金额:
$ 48.86万 - 项目类别:
HIV/Cocaine mediated human pulmonary vascular remodeling: Role of BMPR signaling.
HIV/可卡因介导的人肺血管重塑:BMPR 信号传导的作用。
- 批准号:
8410671 - 财政年份:2012
- 资助金额:
$ 48.86万 - 项目类别:
HIV/Cocaine mediated human pulmonary vascular remodeling: Role of BMPR signaling.
HIV/可卡因介导的人肺血管重塑:BMPR 信号传导的作用。
- 批准号:
8653959 - 财政年份:2012
- 资助金额:
$ 48.86万 - 项目类别:
PDGF-Receptor regulation in Cocaine and Tat mediated Smooth Muscle Hyperplasia
可卡因和 Tat 介导的平滑肌增生中 PDGF 受体的调节
- 批准号:
8231329 - 财政年份:2011
- 资助金额:
$ 48.86万 - 项目类别:
相似海外基金
RESEARCH SUPPORT SERVICES FOR THE DIVISION OF ACQUIRED IMMUNODEFICIENCY SYNDROME
获得性免疫缺陷综合症分类的研究支持服务
- 批准号:
10219039 - 财政年份:2020
- 资助金额:
$ 48.86万 - 项目类别:
RESEARCH SUPPORT SERVICES FOR THE DIVISION OF ACQUIRED IMMUNODEFICIENCY SYNDROME
获得性免疫缺陷综合症分类的研究支持服务
- 批准号:
9981476 - 财政年份:2019
- 资助金额:
$ 48.86万 - 项目类别:
IGF::OT::IGF RESEARCH SUPPORT SERVICES FOR THE DIVISION OF ACQUIRED IMMUNODEFICIENCY SYNDROME
IGF::OT::IGF 针对获得性免疫缺陷综合症分类的研究支持服务
- 批准号:
9364184 - 财政年份:2016
- 资助金额:
$ 48.86万 - 项目类别:
Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS) in Saskatchewan- Where are we now and what does the future hold?
萨斯喀彻温省的人类免疫缺陷病毒(HIV)和获得性免疫缺陷综合症(艾滋病)——我们现在在哪里以及未来会怎样?
- 批准号:
236932 - 财政年份:2011
- 资助金额:
$ 48.86万 - 项目类别:
Miscellaneous Programs
ACQUIRED IMMUNODEFICIENCY SYNDROME RESEARCH REVIEW COMMI
获得性免疫缺陷综合症研究审查委员会
- 批准号:
3554155 - 财政年份:1991
- 资助金额:
$ 48.86万 - 项目类别:
ACQUIRED IMMUNODEFICIENCY SYNDROME RESEARCH REVIEW COMMI
获得性免疫缺陷综合症研究审查委员会
- 批准号:
3554156 - 财政年份:1991
- 资助金额:
$ 48.86万 - 项目类别:
ACQUIRED IMMUNODEFICIENCY SYNDROME RESEARCH REVIEW
获得性免疫缺陷综合症研究综述
- 批准号:
2063342 - 财政年份:1991
- 资助金额:
$ 48.86万 - 项目类别: