TMARC Pilot Studies - Active

The Effect of METH on Neuronal Mitophagy in HIV-1 Infected Brain (Teodorof)

Agency: TMARC
PI: Teodorof, Carmen, Ph.D.

Abstract

Mitophagy is a selective form of autophagy that involves selective sequestration and subsequent degradation of the dysfunctional mitochondria before it causes activation of the cell death. Mitochondria are essential for neuronal survival and function and proper degradation of aged or damaged mitochondria through mitophagy. Viruses manipulate cellular machinery and function to subvert intracellular environment conductive for viral proliferation. Although HIV-1 does not directly infect the neuron, infection of macrophages and microglia with the release viral proteins and inflammatory mediators have been implicated in neuronal dysfunction, and are thought to drive the pathogenesis of HIV-associated neurological disorders. However, the mechanisms leading to dysregulation of mitophagy in central nervous system remain unclear. Although the development of combination antiretroviral therapy has significantly reduced HIV-related disease progression, at least half of the infected individuals are expected to develop some form of neurocognitive impairment. In addition to HIV infection, the abuse of psychostimulants, such as methamphetamine (METH), appears to aggravate neurological disorders and compromise the effectiveness of ART. Antiretrovirals in combination with METH and HIV-1 gp120 compromise neuronal energy homeostasis and mitochondrial function. My research focus is to determine how HIV-1 infection in combination with METH and antiretrovirals drugs alters mitophagy and mitochondrial function in central nervous system and especially in neuronal cells. Experiments will be performed in differentiated SHSY5Y neuronal cells, human primary neurons and human primary neuroglial cells. Dissecting the molecular mechanisms by which HIV utilizes mitophagy may lead to the identification of novel drug candidates to treat and potentially eradicate HIV infection.

Sponsored by NIH/NIDA P50DA026306

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