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Dysregulation of neurogranin, a neuron specific factor, in HIV-1 positive subjects and its implications in HIV-1 associated neurocognitive disorders

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 (Unpublished)

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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.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Hawkins, Christinacbh35@pitt.educbh35
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorAyyavoo, Velpandivelpandi@pitt.edu
Committee MemberMartinson, Jeremyjmartins@pitt.edu
Committee MemberDi, Y.P. Peterpeterdi@pitt.edu
Date: 24 February 2017
Date Type: Publication
Defense Date: 9 December 2016
Approval Date: 24 February 2017
Submission Date: 28 November 2016
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Number of Pages: 61
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Infectious Diseases and Microbiology
Degree: MPH - Master of Public Health
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: HIV, HIV-1, HIV-associated neurocognitive disorders, HAND, neurogranin
Date Deposited: 24 Feb 2017 17:32
Last Modified: 24 Feb 2017 17:32
URI: http://d-scholarship.pitt.edu/id/eprint/30411

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