Targeting Inflammasomes in Substance Abuse and HIV

摘要

ABSTRACT The blood brain barrier (BBB) is a semipermeable cell layer that is essential for brain protection and homeostasis. While the role of endothelial cells in formation of the main physical barrier has been recognized, emerging evidence indicates a critical role of pericytes in maintaining the BBB functions. Evidence indicates that dysfunction of the BBB and disruption of tight junction proteins that regulate BBB integrity are involved in several major mood and psychiatric disorders. BBB pericytes can be a target of HIV infection and support long term replication of the virus in the CNS. Substance abuse, including opioid abuse, is a risk factor for HIV infection and contributes to the development of HIV-associated comorbidities. Indeed, both HIV infection and opioid abuse increase an individual's risk for cerebrovascular disease and ischemic stroke. Due to the position of BBB pericytes in the interplay between HIV and the CNS, we hypothesize that pericyte dysfunction can affect opioid addiction behavior and potentiate ischemic stroke severity in the context of HIV infection. To test this hypothesis, we will employ three different and unique strains of mice that progressively, from modest to severe, exhibit increased BBB permeability and decreased pericyte cell number. We will analyze addiction behavior in pericyte deficient mice through the use of a Conditioned Place Preference test. Tight junction proteins and BBB permeability will be tested in these mice to understand how the BBB can contribute to a change in behavior. Our second aim will focus on studying the impact of pericyte deficiency on paracrine signals critical to BBB health in the context of opioid abuse and studying the influence of pericyte deficiency on ischemic stroke outcomes and recovery. EcoHIV will be delivered into the CNS via the internal carotid artery and exposed to ischemic stroke via middle cerebral artery occlusion. Tissues will be analyzed to determine changes in infarct size and behavioral analysis will be used to study post-stroke recovery. The knowledge gained as the results of our proposal will provide insight into the role of pericytes in cerebrovascular health during HIV infection, opioid abuse, and addiction.