One (1) of the emerging problems in HIV/AIDS is an increase in an older population affected by HIV infection. This phenomenon is of significant concern, because aging is a predictor of rate of progression of HIV infection. Elderly patients develop AIDS more rapidly and have higher morbidity and mortality rates. Older patients are also more likely to develop AIDS-associated dementia. The present research application is focused on the mechanisms that may contribute to the development of dementia in elderly HIV-infected patients. Specifically, we propose to study the mechanisms related to the injury to the vascular endothelium and dysfunction of the blood brain barrier (BBB). Our research has concentrated on the hypothesis that the viral gene product, HIV Tat protein, can be responsible for brain microvascular endothelial cells (BMEC) injury and impaired normal function of the BBB. Furthermore, aging is associated with increased deposits of amyloid P-peptide (AP) which also can induce dysfunction of BMEC. Therefore, it is striking to notice that AB and HIV Tat protein may work in concert in older HIV patients to induce impaired function of the brain vascular endothelium and contribute to the development of neuroAIDS. In the present grant application, we hypothesize that AB and Tat can cross-amplify their cytotoxic effects and exacerbate the disruption of the BBB. Thus, a combined exposure to Ap and Tat can lead to accelerated entry of HIV-1 into the CNS. To study these hypotheses, this research proposal is focused on the pathways related to AP and/or Tat-induced cellular oxidative stress, monocyte transendothelial passage, disruption of expression of cell junction proteins, and decreased barrier function of the BBB. The main in vitro experimental system will consist of the unique and innovative co-cultures of human BMEC with astrocytes which endogenously produce and release Tat. Part of our studies will also employ an animal model of amyloid angiopathy exposed to Tat. The long term goals of the current proposal are to determine mechanisms which may prevent Ap and Tat-induced injury to BMEC. Data arising from this proposal will be critical for a better understanding of mechanisms responsible for disruption of the BBB during HIV-1 infection associated with aging. In a broader aspect, this proposal will contribute to better knowledge of how aging can contribute to the development of neurological complications of HIV/AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH072567-04
Application #
7492669
Study Section
Special Emphasis Panel (ZRG1-AARR-A (05))
Program Officer
Joseph, Jeymohan
Project Start
2005-09-20
Project End
2010-08-31
Budget Start
2008-09-01
Budget End
2010-08-31
Support Year
4
Fiscal Year
2008
Total Cost
$277,817
Indirect Cost
Name
University of Kentucky
Department
Surgery
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
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 :
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
Eum, Sung Yong; Jaraki, Dima; András, Ibolya E et al. (2015) Lipid rafts regulate PCB153-induced disruption of occludin and brain endothelial barrier function through protein phosphatase 2A and matrix metalloproteinase-2. Toxicol Appl Pharmacol 287:258-66
Bertrand, Luc; Toborek, Michal (2015) Dysregulation of Endoplasmic Reticulum Stress and Autophagic Responses by the Antiretroviral Drug Efavirenz. Mol Pharmacol 88:304-15

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