The blood-brain barrier (BBB) is the most prominent barrier of the CNS and represents the essential interface between the CNS and the blood stream. The intact BBB is maintained by tight junction (TJ) proteins and is a paramount determinant of brain homeostasis. Disruption of the BBB is frequently observed during drug abuse and brain infections by various pathogens, including HIV. Our critically important results indicate that occludin, one of the major TJ proteins, is decreased upon methamphetamine (METH) exposure and that diminished occludin levels not only lead to the loss of integrity of the BBB but also stimulate HIV replication. The proposed research is built on these exciting findings by its focus on the central hypothesis that cerebrovascular alterations at the BBB level induced by METH have profound impact on establishing and outcome of the brain infection by HIV. Guided by the preliminary findings, this application offers a unique perspective on the interactions between METH and HIV via targeting the BBB.
In Aim 1, we will evaluate the impact of METH-induced decrease in occludin expression on activation of NF-B and SP-1, enhancing interactions of this transcription factors with the HIV long-terminal repeats (LTRs) and thus stimulating HIV replication.
In Aim 2, we will study the impact of METH and HIV-induced disruption of BBB on aberrant neurogenesis of neural progenitor cells resulting in the development of cognitive dysfunction.
Aim 3 will focus on behavioral intervention based on exercise for protection against METH and HIV-induced BBB dysfunction and neurocognitive alterations. The proposed research is highly innovative and is likely to lead to the development of new translational knowledge for the clinic and identification of new regulatory mechanisms of HIV replication. The completion of this application has the potential to change our understanding of the cellular role of occludin in HIV infection and the role of the BBB in the development of METH and/or HIV-associated cognitive dysfunction. Furthermore, the expected results are likely to be also relevant to other neurodegenerative diseases that have significant cerebrovascular components.

Public Health Relevance

This application is focused on the central hypothesis that cerebrovascular alterations at the blood-brain barrier (BBB) levels induced by methamphetamine abuse have profound impact on establishing and outcome of the brain infection by HIV. This notion will be studied in the context of HIV replication (Aim 1), impaired neurogenesis (Aim 2), and exercise-mediated protection (Aim 3). The obtained results are likely to provide new therapeutic approaches to protect against brain infection by HIV during drug abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA039576-02
Application #
8996684
Study Section
Special Emphasis Panel (ZDA1)
Program Officer
Purohit, Vishnudutt
Project Start
2015-04-01
Project End
2020-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Biochemistry
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Skowronska, Marta; McDonald, Marisa; Velichkovska, Martina et al. (2018) Methamphetamine increases HIV infectivity in neural progenitor cells. J Biol Chem 293:296-311
Bertrand, Luc; Dygert, Levi; Toborek, Michal (2017) Induction of Ischemic Stroke and Ischemia-reperfusion in Mice Using the Middle Artery Occlusion Technique and Visualization of Infarct Area. J Vis Exp :
Cho, Hyung Joon; Kuo, Alyce Mei-Shiuan; Bertrand, Luc et al. (2017) HIV Alters Gap Junction-Mediated Intercellular Communication in Human Brain Pericytes. Front Mol Neurosci 10:410
András, Ibolya E; Leda, Ana; Contreras, Marta Garcia et al. (2017) Extracellular vesicles of the blood-brain barrier: Role in the HIV-1 associated amyloid beta pathology. Mol Cell Neurosci 79:12-22
Leda, Ana R; Dygert, Levy; Bertrand, Luc et al. (2017) Mouse Microsurgery Infusion Technique for Targeted Substance Delivery into the CNS via the Internal Carotid Artery. J Vis Exp :
Tomitaka, Asahi; Arami, Hamed; Raymond, Andrea et al. (2017) Development of magneto-plasmonic nanoparticles for multimodal image-guided therapy to the brain. Nanoscale 9:764-773
Bertrand, Luc; Dygert, Levi; Toborek, Michal (2016) Antiretroviral Treatment with Efavirenz Disrupts the Blood-Brain Barrier Integrity and Increases Stroke Severity. Sci Rep 6:39738
Park, Minseon; Levine, Harry; Toborek, Michal (2016) Exercise protects against methamphetamine-induced aberrant neurogenesis. Sci Rep 6:34111
Castro, Victor; Bertrand, Luc; Luethen, Mareen et al. (2016) Occludin controls HIV transcription in brain pericytes via regulation of SIRT-1 activation. FASEB J 30:1234-46
András, Ibolya E; Toborek, Michal (2016) Extracellular vesicles of the blood-brain barrier. Tissue Barriers 4:e1131804

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