eprintid: 30411
rev_number: 45
userid: 6313
dir: disk0/00/03/04/11
datestamp: 2017-02-24 17:32:28
lastmod: 2017-02-24 17:32:28
status_changed: 2017-02-24 17:32:28
type: thesis_degree
metadata_visibility: show
contact_email: cbhawkin@g.cofc.edu
eprint_status: archive
creators_name: Hawkins, Christina
creators_email: cbh35@pitt.edu
creators_id: cbh35
title: Dysregulation of neurogranin, a neuron specific factor, in HIV-1 positive subjects and its implications in HIV-1 associated neurocognitive disorders
ispublished: unpub
divisions: sch_gsph_infectiousdiseasesmicrobiology
full_text_status: restricted
keywords: HIV, HIV-1, HIV-associated neurocognitive disorders, HAND, neurogranin
abstract: Description of The Problem:
The HIV/AIDS epidemic is an issue of public health relevance due to the widespread prevalence of the disease and the difficulty in treatment. Thirty million individuals worldwide are currently living with HIV, and approximately one million of those infected die each year from AIDS-related illnesses. While improvements in medication and therapy have increased the lifespan of HIV-1 positive individuals and reduced the severity of symptoms, more than half of HIV-1 positive subjects continue to suffer from HIV-associated neurocognitive disorders (HAND). Even individuals undergoing combination anti-retroviral therapy (cART) that have an undetectable viral load suffer from HAND, suggesting cART is unable to prevent neuronal dysfunction. The resulting cognitive deficits can burden the daily functioning of HIV-1 positive subjects and constitute an issue in great need of further research.
Objectives:
Our preliminary studies have shown that the neuron specific protein, Neurogranin (Nrgn), is dysregulated in the brains of HIV-1 positive subjects. Nrgn is a protein important in the Ca2+/calmodulin signaling pathway and long-term potentiation (LTP) in the brain. However, it is not clear how HIV-1 infection alters Nrgn and its function. Based on what is known, we hypothesize that both viral and virus influenced cellular factors contribute in part to the dysregulation of Nrgn and the development of HAND.
Methods Used:
I propose to investigate how viral protein mediated cellular effects may contribute to Nrgn regulation. Using macrophages infected with a wild type virus as well as viruses deficient in Nef, Env, Vpr, or Vif protein expression, I propose to evaluate how these viral proteins and inflammatory factors (cytokines/chemokines) released from HIV-1 infected cells affect Nrgn expression.
Results:
Our results show differences in the secreted concentration of human IL-8, as well as the expression of Nrgn in cells exposed to each HIV-1 virus type studied. HIV-1 wild type virus upregulated IL-8 and dysregulated Nrgn at a higher level compared to other viral mutants. While future studies need to be conducted to confirm these results, our study provides evidence that both viral proteins and secreted cellular factors may contribute to the dysregulation of Nrgn.
Conclusions:
By increasing our understanding of the role of viral proteins and inflammatory factors in Nrgn expression, we can better understand how HIV-1 dysregulates Nrgn in the brains of infected individuals and illuminate potential therapeutic targets to reduce the development of HAND.
date: 2017-02-24
date_type: published
pages: 61
institution: University of Pittsburgh
refereed: TRUE
etdcommittee_type: thesis_advisor
etdcommittee_type: committee_member
etdcommittee_type: committee_member
etdcommittee_name: Ayyavoo, Velpandi
etdcommittee_name: Martinson, Jeremy
etdcommittee_name: Di, Y.P. Peter
etdcommittee_email: velpandi@pitt.edu
etdcommittee_email: jmartins@pitt.edu
etdcommittee_email: peterdi@pitt.edu
etd_defense_date: 2016-12-09
etd_approval_date: 2017-02-24
etd_submission_date: 2016-11-28
etd_release_date: 2017-02-24
etd_access_restriction: 5_year
etd_patent_pending: FALSE
thesis_type: thesis
degree: MPH
citation:   Hawkins, Christina  (2017) Dysregulation of neurogranin, a neuron specific factor, in HIV-1 positive subjects and its implications in HIV-1 associated neurocognitive disorders.  Master's Thesis, University of Pittsburgh.    (Unpublished)  
document_url: http://d-scholarship-dev.library.pitt.edu/30411/1/ChristinaBarrettHawkins_ETD2016.pdf