Grants and Contracts Details
Description
Neurological disorders associated with HIV-1 affect 40-70% of infected individuals and is characterized as HIV-
1-associated neurocognitive disorders (HAND). While antiretroviral therapy (ART) has diminished disease
severity, milder forms of cognitive impairment remain commonplace. It is critical to discover new therapeutic
strategies to fully prevent the neurocognitive impairment. Active neurogenesis occurs throughout life and relies
upon the proliferation, migration, and proper differentiation of neural stem/progenitor cells (NPCs). Under
pathological conditions of the central nervous system (CNS) associated with neuroinflammation such as
HAND, monocytes/macrophages infiltrating the CNS in concert with activated resident microglia play a major
role in the neurodegenerative process of HAND. Activated macrophage/microglia produce inflammatory
mediators such as cytokines and chemokines, affect the capacity of brain stem cells and alter neurogenesis.
Various types of macrophage/microglia activation, depending on the conditions, can either enhance or
suppress neurogenesis. Inflammation-associated M1 macrophages/microglia can inhibit neurogenesis;
whereas IL-4-activated M2 macrophages/microglia can induce both neurogenesis and oligodendrogenesis. In
HAND, HIV-1 infection in the brain inhibits neurogenesis with generation of fewer adult NPCs in the dentate
gyrus of the hippocampus. Moreover, NPCs preferably differentiate into astrocytes rather than neurons. Our
previous studies demonstrated HIV-1-infected and LPS-activated (M1) Macrophages inhibit neurogenesis,
while enhancing gliogenesis through secretion of inflammatory cytokines such as IL-1â and TNF-á. microRNA-
124 (miR-124) has recently been shown to deactivate M1 macrophages and skew their polarization from an
M1 toward an M2 phenotype. miR-124 may serve as a useful tool to transfer detrimental pro-inflammatory M1
macrophages/microglia to beneficial M2 macrophages/microglia. Therefore, we propose the following specific
aims: Aim 1: To investigate how miR-124 deactivates HIV-1-infected M1 macrophages/microglia or polarizes
them to an M2 phenotype and promotes neurogenesis in vitro. Aim 2: To investigate the therapeutic potential
of miR-124 for ameliorating HIV-1-infection-mediated inhibition of neurogenesis in HIV-1 encephalitis (HIVE)
and humanized mouse models. We will test our hypothesis using primary human NPC, macrophage/microglia
culture systems, and HIVE and humanized mouse models. This novel system mimics the HIV-1-infection and
immune-activation of brain macrophage/microglia as they occur within the CNS during HAND. We will validate
the effect of miR-124 on modulating macrophage/microglia activation and its subsequent effect on
neurogenesis in vitro and in vivo. The data generated from this study will help to identify a highly innovative
strategy for HAND therapy. Furthermore, these findings will provide insight into a range of other
neurodegenerative and neuroinflammatory diseases in which macrophage/microglia activation plays an
important role.
Status | Finished |
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Effective start/end date | 7/1/14 → 6/30/17 |
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