eprintid: 34155
rev_number: 42
userid: 7579
dir: disk0/00/03/41/55
datestamp: 2018-09-17 20:35:43
lastmod: 2018-09-17 20:35:43
status_changed: 2018-09-17 20:35:43
type: thesis_degree
metadata_visibility: show
contact_email: xiaorjrj@126.com
eprint_status: archive
creators_name: Xiao, Renjian
creators_email: REX4@pitt.edu
creators_id: rex4
title: Neuroprotective micrornas combat HIV-1 associated neurocognitive disorder (HAND) pathogenesis
ispublished: unpub
divisions: sch_gsph_infectiousdiseasesmicrobiology
full_text_status: restricted
keywords: miRNA, THP1, microglia, HAND, HIV-1
abstract: HIV-1 associated neurocognitive disorder (HAND) is one of the major HIV-1 co- morbidities prevalent around the world. Early during HIV-1 infection, virus crosses the blood - brain barrier (BBB) and enters central nervous system (CNS) through infiltrating infected monocytes/macrophages. These infiltrating infected monocytes/macrophages serve as the source to initiate secondary infection of resident monocytic cells and glial cells in CNS. Neurons are not directly infected by HIV-1 virus. However, pro-inflammatory cytokines and chemokines as well as viral proteins released by infected/exposed immune and glial cells are neurotoxic and contribute to the neuronal stress and apoptosis. Nearly more than half of individuals living with HIV-1 infection present with some degree of neuronal impairment. Currently, no treatment is available to prevent or treat HAND. Thus, devising a strategy to manage HAND progression and improve the quality of life in HIV-1 positive population will be highly valuable and is of great public health significance.
MicroRNAs are small non-coding RNAs which play an important role in post- transcriptional regulation. Previous studies in our laboratory have identified specific miRNAs that may have a neuro-protective role. In this study, my goal is to evaluate the role of these candidate miRNAs on inflammatory response of monocytes/macrophages and microglia during HIV-1 infection. I hypothesize that these candidate miRNAs can reduce the proinflammatory response of monocytes/macrophages and microglia, and these inhibitory effects of miRNAs are conserved during HIV-1 infection. In order to test this hypothesis, candidate miRNAs were over expressed in monocytic cell line (THP1) and microglia by using lentiviral expression vectors. Results suggest that miR-20a and miR-106b expression in monocytic cell lines inhibits TNF-α production, while miR-let-7a significantly downregulates IL-6 secretion in response to LPS either in the presence or absence of HIV-1 infection. Similarly, in microglia cells, miR-106b inhibits both IL-6 and IL-8 secretion upon LPS stimulation and miR-20a reduces IL-6 production upon TNF-α stimulation. Evaluation of these candidate miRNAs in J-Lat cells, which contain a single copy of HIV-1 latent HIV-1 virus suggest that, miR-20a, miR-106b, miR-124 and let-7a were able to reduce HIV-1 reactivation. These results indicate that neuroprotective miRNAs may have a direct role in reducing specific neuroinflammatory factor production and may also affect HIV- 1 virus production. Thus, these candidate miRNAs could have a potential therapeutic role to minimize neuroinflammatory cytokine induced neuronal dysfunction and thus aid in management of HAND.
date: 2018-09-17
date_type: published
pages: 66
institution: University of Pittsburgh
refereed: TRUE
etdcommittee_type: committee_chair
etdcommittee_type: committee_member
etdcommittee_type: committee_member
etdcommittee_name: Ayyavoo, Velpandi
etdcommittee_name: Chen, Yue
etdcommittee_name: Jenkins, Frank
etdcommittee_email: velpandi@pitt.edu
etdcommittee_email: cheny@pitt.edu
etdcommittee_email: fjenkins@pitt.edu
etdcommittee_id: velpandi
etdcommittee_id: cheny@pitt.edu
etdcommittee_id: fjenkins
etd_defense_date: 2018-04-24
etd_approval_date: 2018-09-17
etd_submission_date: 2018-04-05
etd_release_date: 2018-09-17
etd_access_restriction: 3_year
etd_patent_pending: FALSE
thesis_type: thesis
degree: MS
citation:   Xiao, Renjian  (2018) Neuroprotective micrornas combat HIV-1 associated neurocognitive disorder (HAND) pathogenesis.  Master's Thesis, University of Pittsburgh.    (Unpublished)  
document_url: http://d-scholarship-dev.library.pitt.edu/34155/1/XiaoRenjian_MSthesis_6_2018.pdf