Novel role of inflammasome activation in ART neurotoxicity

Project: Research project

Project Details

Description

ABSTRACT Toxicity of ART contributes to brain pathology and cognitive decline observed in HIV-infected individuals; however, the mechanisms are not fully understood. The importance of ART toxicity has been further enhanced by the introduction of pre-exposure prophylaxis (PrEP) into HIV prevention. The blood-brain barrier (BBB) is on the first line of exposure to antiretroviral drugs, making the brain endothelium particularly relevant in studies on toxicity of ART. While antiretroviral drugs frequently achieve only sub-therapeutic levels in the brain parenchyma, their plasma concertations are sufficient to negatively impact the brain vasculature, making the brain endothelium the main target of ART toxicity in the CNS. The current application is based on our exciting findings indicating that ART exposure results in mitochondrial dysfunction and alterations of neurogenesis of neural progenitor cells (NPCs). Mitochondrial dysregulation is a strong inducer of inflammasome, and indeed, our results implicate inflammasome activation in ART-induced cerebral vascular toxicity. Mechanistically, the proposed work is focused on a novel pathway of intercellular communication between the brain endothelium and perivascular NPCs via activation of inflammasome. The central hypothesis is that ART activates inflammasome in brain endothelial cells, followed by release of IL1?, which then affects adult neurogenesis of NPCs, diminishing their differentiation into mature neurons and contributing to cognitive decline. Throughout the proposal, we will differentiate the impact of ART with high CNS penetrating efficacy (CPE) vs. ART with low CPE. Our application offers a unique, mechanistic, and translational perspective on ART-induced toxicity and neuroinflammation that results in cognitive impairment. The completion of the proposed study promises to establish new therapeutic targets to protect against toxicity of ART.
StatusActive
Effective start/end date3/1/212/28/22

Funding

  • National Institute of Mental Health: $191,875.00

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