Graduation Date

Fall 12-20-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Medical Sciences Interdepartmental Area

First Advisor

Shilpa Buch

Second Advisor

Howard Fox

Third Advisor

Georgette Kanmogne

Fourth Advisor

Paras Mishra

Abstract

Neuronal damage and neuroinflammation is a hallmark feature of HIV-associated neurological disorders (HANDs). Opioids abuse accelerates the incidence and progression of HAND; however, the mechanisms underlying the potentiation of neuropathogenesis by these drugs remain elusive. Extracellular vesicles (EVs) are essential conduits in HIV and drug abuse-mediated synaptodendritic injury and neuroinflammation. Findings from our group have demonstrated that astrocyte-derived EV (ADEV)-miRNA-29b mediates HIV Tat and morphine-induced neuronal injury, thus underscoring the importance of such interactions in NeuroHIV.

Besides, HIV Tat and morphine-mediated synaptodendritic injury via ADEVs, we are also interested in whether ADEVs contributes to neuroinflammation. Microglia are critical players in neuroinflammation. Morphine could regulate microglial function; However, the role of ADEVs in morphine-mediated dysregulation of microglia remains elusive. Additionally, drugs of abuse such as opioids can result in a breach of the blood-brain barrier (BBB), ultimately leading to enhanced monocyte transmigration and ensuing neuroinflammation. Recently studies provide compelling evidence that pericyte loss on the microvessels results in increased extravasation of peripheral immune cells. Mechanism(s) by which pericytes contribute to morphine-mediated neuroinflammation, however, remains less understood.

The overarching goal of this thesis is to explore another undefined role of the morphine-mediated release of EV-miRNAs in regulating microglial and pericyte function(s), which, in turn, leading to neuroinflammation. We found that 1) morphine stimulated ADEVs can be taken up by microglial cells, leading, in turn, to impaired microglial phagocytosis via the TLR7-NF-kB -lincRNA-Cox2 axis and intranasal delivery of lincRNA-Cox2 siRNA restored microglial phagocytic activity of morphine-administered mice; 2) exposure of astrocytes in culture to morphine resulted in increased expression and secretion of miR-138 in the ADEVs which in turn, were taken up by the microglia, resulting in microglial activation, via binding to endosomal TLR7; 3) exposure of astrocytes to morphine resulted in induction and release the of miR-23a in the ADEVs, which, taken up by pericytes, leading to loss of pericyte thus lead to influx of monocyte (Figure 1).

Our findings could have clinical ramifications in the future for developing EV-loaded RNA-based therapeutics that aimed at managing neuroinflammation-associated cognitive disorders in the context of chronic morphine abuse and HIV-opiate comorbidities.

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