Active neurogenesis occurs throughout life and relies upon the proliferation, migration and proper differentiation of neural stem/progenitor cells (NPCs). Diminished adult neurogenesis is considered a potential factor in the pathogenesis of HIV-1-associated dementia (HAD). In HAD, HIV-1-infected and immune-activated brain mononuclear phagocytes (MP;perivascular macrophages and microglia) drive central nervous system (CNS) inflammation and may alter normal neurogenesis. We previously demonstrated HIV-1-infected and activated MP inhibit neurogenesis, while enhancing astrogliogenesis in vitro and in vivo, through secretion of inflammatory cytokines such as IL-1b and TNF-a. Our preliminary study showed both IL-1b and TNF-a, as well as HIV-1-infected and LPS-activated MP induced STAT3 activation, a critical pathway of astrogliogenesis. Furthmore, microRNA-9 (miR-9) and brain-specific microRNA-124 (miR-124), factors shown to inhibit STAT3 activation, promote neuronal differentiation and inhibit astrocyte differentiation, are decreased in response to cytokine (IL-1b and TNF-a) treatment. Based on these observations, we hypothesize that HIV-1-infected and immune-activated MP promote NPC astrogliogenesis through secreted factors including cytokines (IL-1b and TNF-a) via the STAT3 pathway, and that miR-9 and miR-124 regulate this process through modulation of STAT3 activation. In this proposal, we will study the STAT3 pathway in NPCs following stimulation with inflammatory cytokines (including IL-1b and TNF-a) and HIV-1-infected and immune-activated MP and examine the effect on astrogliogenesis. We will also investigate the role of miRNAs (miR-9 and miR-124) in STAT3 activation and the modulation of human NPC differentiation mediated by cytokines (IL-1b and TNF-a) and HIV-1-infected and activated MP. We will test this hypothesis using a primary human NPC culture system and a severe combined immune deficient (SCID) HIV-1 encephalitis (HIVE) mouse model. This research will generate important data deciphering the role of brain inflammation in neurogenesis during progressive HIV-1 infection of the CNS. In addition, the work will also identify potential targets for therapeutic intervention for neural stem cell therapy.

Public Health Relevance

Diminished adult neurogenesis is considered a potential factor in the pathogenesis of HIV-1-associated dementia, in which HIV-1-infected and immune-activated macrophages drive central nervous system (CNS) inflammation. The study of the factors produced by these inflammatory cells and the signaling pathways involved in neural stem/progenitor cell differentiation will generate important data deciphering the role of brain inflammation in neurogenesis during progressive HIV-1 infection of the CNS, and identify potential targets for therapeutic intervention for neural stem cell therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS066841-01A1
Application #
7841436
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2009-09-28
Project End
2011-07-31
Budget Start
2009-09-28
Budget End
2010-07-31
Support Year
1
Fiscal Year
2009
Total Cost
$222,750
Indirect Cost
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198