Drug abuse and HIV-associated pulmonary vascular injury
药物滥用和 HIV 相关肺血管损伤
基本信息
- 批准号:10330405
- 负责人:
- 金额:$ 60.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-02-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AIDS/HIV problemAnimal ModelApoptosisApoptoticBCL1 OncogeneBCL2L1 geneBindingBioinformaticsBiological AssayBiological ProcessBloodBlood VesselsCardiopulmonaryCell Culture TechniquesCell Cycle ProgressionCell ProliferationChronic Obstructive Pulmonary DiseaseCocaineCombined Modality TherapyDataDetectionDevelopmentDrug abuseEarly DiagnosisExposure toFunctional disorderGenesHIVHIV-1HealthHeartHumanHyperplasiaIllicit DrugsIndividualKansasLightLinkLungMacacaMediatingMedical centerMicroarray AnalysisModelingPathogenesisPathogenicityPatientsPhenotypePrevalencePreventiveProtein IsoformsProteinsPublishingPulmonary EmphysemaPulmonary HypertensionRNARNA SplicingRNA-Binding ProteinsRattusRegulationReportingResearchResearch InstituteResistanceRight Ventricular DysfunctionRiskRoleSIVSleepSmooth MuscleSmooth Muscle MyocytesStructure of parenchyma of lungStudy modelsSystolic PressureTherapeutic InterventionTransgenic OrganismsUniversitiesUntranslated RNAUp-RegulationVascular DiseasesVascular remodelingVentricularantiretroviral therapybasecell growthcell typecocaine exposurecomorbiditydifferential expressiondrug abuserdrug of abusegene repressionin vivoinhibitorinnovationintravenous drug userknock-downlung vascular injurymRNA Expressionnew therapeutic targetnon-drugnovelpre-clinicalpreventpulmonary arterial hypertensionpulmonary arterial pressurepulmonary vascular disorderpulmonary vascular remodelingresponseright ventricular failuretumorvascular injury
项目摘要
PROJECT SUMMARY
University of Kansas Medical Center Research Institute, Inc.
Advancement in antiretroviral therapy (ART) has clearly led to a serious increase in the prevalence of non-
infectious cardio-pulmonary complications among HIV-infected individuals including chronic obstructive
pulmonary disease (COPD) and HIV-related pulmonary arterial hypertension (HIV-PAH). In fact, recent reports
suggest that pulmonary vascular remodeling and pulmonary hypertension (PH) precede the airway
destruction/emphysema development and that PH and COPD coexist in HIV-infected individuals. Significant
number of previous findings including from our lab consistently suggest increased risk for pulmonary vascular
dysfunction in HIV-infected individuals who abuse illicit drugs compared to HIV-infected non-drug users or un-
infected drug abusers. Understanding the mechanisms by which cocaine and HIV-1 trigger pulmonary vascular
injury is needed to develop preventive and early diagnosis strategies for patients at risk of HIV-PAH.
Pulmonary arterial smooth muscle cells (PASMCs) are one of the primary cell-types that undergo hyperplasia
during vascular remodeling. The salient finding in all our published reports is the synergistic or additive
enhancement in the proliferation of PASMCs exposed to both HIV protein(s) and cocaine. Recently, long
noncoding RNAs (LncRNAs) have emerged as important regulators of diverse biological process including cell
proliferation and apoptosis. Based on our published and recent preliminary findings we hypothesize that
alteration in the levels of lncRNA:ENST-536 in response to HIV-protein(s) and/or cocaine in smooth muscle
cells promote pulmonary vascular remodeling and cardio-pulmonary complications. In the first aim we will
examine if changes in the expression of ENST-536 lncRNA and its nearby tumor suppressive gene, HOXB13
regulate the HIV-Tat and cocaine mediated changes in the smooth muscle phenotype. In the second aim, we
will investigate how the interactions between lncRNA ENST-536 and RNA binding protein(s) (RBP) regulate
the HIV-Tat and cocaine mediated smooth muscle dysfunction.Third aim will be focused on investigating the in-
vivo role of lncRNA ENST-536 and HOXB13 in the pulmonary vascular dysfunction and right ventricular failure
using pre-clinical animal model 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 LncRNA, RBP and HOXB13 in the HIV-1
and/or cocaine mediated pulmonary vascular remodeling. The proposed research is significant because it will
enhance our understanding of pathogenic mechanisms involved in the development of HIV-PAH and will fulfill
the purpose of NOT-HL-19-677 (SEARCH: Stimulating ExplorAtory Research on HIV/AIDS Contribution
to Heart, Lung, Blood and Sleep Comorbidities) in search of novel mechanisms involved in HIV-associated
comorbidities.
项目总结
堪萨斯大学医学中心研究所。
抗逆转录病毒疗法(ART)的进步明显导致非霍奇金淋巴瘤患病率的严重增加
HIV感染者的感染性心肺并发症,包括慢性阻塞性
肺部疾病(COPD)和艾滋病毒相关性肺动脉高压(HIV-PAH)。事实上,最近的报道
提示肺血管重塑和肺动脉高压先于呼吸道
在感染艾滋病毒的人中,肺气肿和慢性阻塞性肺病共存。意义重大
包括我们实验室在内的许多以前的发现一直表明肺血管风险增加
与HIV感染者、非吸毒者或非吸毒者相比,滥用非法药物的HIV感染者的功能障碍
被感染的吸毒者。了解可卡因和HIV-1触发肺血管的机制
需要为有艾滋病毒-PAH风险的患者制定预防和早期诊断策略。
摘要肺动脉平滑肌细胞(PASMCs)是细胞增殖的主要类型之一。
在血管重塑期间。在我们所有已发表的报告中,突出的发现是协同或相加
HIV蛋白和可卡因对PASMC增殖的促进作用(S)。最近,龙
摘要非编码RNA是包括细胞在内的多种生物过程的重要调节因子。
增殖和凋亡。根据我们已发表的和最近的初步发现,我们假设
人类免疫缺陷病毒蛋白(S)和/或可卡因对血管内皮细胞LncRNA:ENST-536表达水平的影响
细胞促进肺血管重塑和心肺并发症。在第一个目标中,我们将
检测ENST-536 LncRNA及其邻近抑癌基因HOXB13的表达变化
调节HIV-TAT和可卡因介导的平滑肌表型变化。在第二个目标中,我们
将研究lncRNAENST-536和RNA结合蛋白(S)(RBP)之间的相互作用是如何调节的
HIV-TAT和可卡因介导的血管平滑肌功能障碍。
IncRNA ENST-536和HOXB13在肺血管功能障碍和右心衰竭中的活体作用
使用临床前动物模型,这些研究是创新的,因为据我们所知,它将是
首次尝试了解lncRNA、RBP和HOXB13在HIV-1中的作用之间的潜在联系
和/或可卡因介导的肺血管重塑。这项拟议的研究意义重大,因为它将
加强我们对艾滋病毒-多环芳烃发病机制的了解,并将履行
NOT-HL-19-677的目的(搜索:激励对艾滋病毒/艾滋病贡献的探索性研究
心、肺、血和睡眠并存)寻找与HIV相关的新机制
合并症。
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)
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Navneet Kaur Dhillon其他文献
Navneet Kaur Dhillon的其他文献
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{{ 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:
10799336 - 财政年份:2021
- 资助金额:
$ 60.05万 - 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:
$ 60.05万 - 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:
$ 60.05万 - 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:
$ 60.05万 - 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:
$ 60.05万 - 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:
9115350 - 财政年份:2015
- 资助金额:
$ 60.05万 - 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:
$ 60.05万 - 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:
$ 60.05万 - 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:
$ 60.05万 - 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:
$ 60.05万 - 项目类别:
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