Brain inflammation underlies the neuropathogenesis of HIV-1 infection. The inflammatory mechanism driving neurological disease and neuronal injury affects multiple neurodegenerative disorders including HIV-1-associated dementia (HAD). One important and newly discovered inflammatory and neurotoxic mediator implicated in the pathogenesis of HAD is glutaminase. Glutaminase catalyzes the deamination of glutamine to glutamate and is generally localized to the inner membrane of the mitochondria. Recently, we demonstrated that glutamate is upregulated by HIV-infected, immune-activated monocyte derived macrophages (MDM) and this neurotoxic increase in glutamate represents a major contribution to macrophage-mediated neurotoxicity. Importantly, glutaminase activity is required for glutamate production, and glutaminase-specific siRNA and small-molecule glutaminase inhibitors effectively prevent excess glutamate production. Moreover, the glutaminase isoform glutaminase C (GAC) is upregulated in HIV-1-infected MDM, and GAC release may be involved in increased glutamate production. HIV-1 infection also decreases the levels of expression of microRNA-23a/b, a glutaminase-targeting member of non- coding RNAs, in HIV-1 infected MDM. Further, cytokines such as TNF-1 and IFN-1, produced by HIV-1-infected and immune-activated macrophages increase glutaminase isoform kidney type glutaminase (KGA) expression in neurons, which could potentiate macrophage mediated neurotoxicity during HIV-1 infection. Based on these preliminary results, this competitive renewal proposal will examine the hypothesis that an important event in HAD is the increase of glutaminase expression and release, mediated by inflammation and mitochondria stress during HIV- 1 infection. We argue that this is a significant pathogenic event that triggers macrophage-neuron interactions and affects signaling events eventually leading to increased brain glutamate levels and excitotoxic neuronal damage. This project will develop assays that investigate brain macrophage activation, miRNA23a/b regulation, mitochondrial stress and neuronal injury that occur in HAD. A drug delivery system including a copolymer conjugated with glutaminase and mitochondrial stress inhibitors will be examined in a severe combined immune deficient HIV-1 encephalitis mouse model. The elucidation of the mechanisms by which glutaminase mediates neuronal injury during HIV-1 infection will aid in developing potential new therapeutic agents and drug delivery systems for the treatment of HAD.

Public Health Relevance

Globally, about 40 million people are infected with HIV. 10-20% of these individuals will eventually develop HIV-1 associated neurocognitive disorders (HAND). This work will elucidate mechanisms through which glutaminase play in neuronal injury during HAND, which could identify new therapeutic strategies for treating HAND and other neurodegenerative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041858-13
Application #
8445266
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2001-06-01
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
13
Fiscal Year
2013
Total Cost
$351,091
Indirect Cost
$114,666
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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