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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：
10161471
负责人：
Navneet Kaur Dhillon
金额：
$ 68.95万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
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：
https://reporter.nih.gov/project-details/10161471
关键词：
AIDS/HIV problem Animal Model Apoptosis Apoptotic BCL1 Oncogene Binding Bioinformatics Biological Assay Biological Process Blood Blood Vessels Cardiopulmonary Cell Culture Techniques Cell Cycle Progression Cell Proliferation Chronic Obstructive Airway Disease Cocaine Combined Modality Therapy Data Detection Development Drug abuse Early Diagnosis Exposure to Failure Functional disorder Genes HIV HIV-1 Health Heart Heart failure Human Hyperplasia Illicit Drugs Individual Kansas Light Link Lung Macaca Mediating Medical center Microarray Analysis Modeling Pathogenesis Pathogenicity Patients Phenotype Prevalence Preventive Protein Isoforms Proteins Publishing Pulmonary Emphysema Pulmonary Hypertension RNA RNA Splicing RNA-Binding Proteins Rattus Regulation Reporting Research Research Institute Resistance Right Ventricular Dysfunction Risk Role SIV Sleep Smooth Muscle Smooth Muscle Myocytes Structure of parenchyma of lung Study models Systolic Pressure Therapeutic Intervention Transgenic Organisms Universities Untranslated RNA Up-Regulation Vascular Diseases Vascular remodeling Ventricular antiretroviral therapy base cell growth cell type cocaine exposure comorbidity differential expression drug abuser drug of abuse gene repression in vivo inhibitor/antagonist innovation intravenous drug user knock-down mRNA Expression new therapeutic target non-drug novel pre-clinical pressure prevent pulmonary arterial hypertension response tumor vascular 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