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Methamphetamine actions on recovery of the BBB damage related to HIV

Award Number: R21DA043448
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2018
PERIOD OF PERFORMANCE END DATE: 04/30/2022

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Methamphetamine actions on recovery of the BBB damage related to HIV - Project Summary: HIV infection can damage the endothelial lining of vessels, including those that form the blood-brain barrier (BBB). Methamphetamine (METH) is a widely abused psychostimulant, whose abuse is a detrimental co- morbidity with HIV infection. To date, research has focused on the neurotoxic effects of METH. However, in addition to causing the death of neurons, METH can induce apoptosis in a variety of cell types, including immune cells, glial cells, stem cells, and brain microvascular endothelial cells (BMVECs). Both in vitro and in vivo studies have determined that METH disrupts the integrity of the BBB by decreasing expression of structural proteins and increasing permeability. METH’s effects appear to be dose dependent. At neurotoxic levels, METH induces apoptosis of the BMVECs that line the BBB, causing BBB damage. At a lower dose, METH inhibits proliferation and differentiation of endothelial progenitor cells (EPCs), which could negatively affect the endogenous recovery process of the damaged endothelium. While studies have shown that METH damages BMVECs, few, if any, studies have examined the effects of METH on the repair and restoration of an already-damaged BBB such as HIV-induced BBB damage. This research deficit is primarily due to the lack of an adequate experimental animal model. We have recently developed an intermedilysin (ILY) cell ablation model to mimic the endothelial injury induced in the pathological conditions. In our protocol, an endothelial cell- specific partial ablation model is first generated using a non-lethal dose of ILY in HIV-1 transgenic mice (HIVTg26 mice). EPCs prepared from commercially available “enhanced” green fluorescent protein (EGFP) transgenic mice can then be transplanted into that model. The EPCs differentiate into endothelial cells to restore the partially damaged endothelial cell lining and recover the integrity of the BBB. The location of transplanted EPCs and progression of BBB recovery can be monitored by the EGFP upon excitation light. We propose to use our endothelial cell ablation model in HIVTg26 mice to mimic the damaged endothelium that occurs in disease states such as HIV infection in order to test our working hypothesis that the repair of the endothelial cell lining of a damaged BBB by EPCs is impeded by METH and worsened in the presence of HIV viral proteins. Our specific aims are to investigate: 1) the effects of METH on the repair and restoration of the damaged endothelial cell lining of the BBB in the presence of HIV viral proteins in vivo (Aim 1); and 2) the molecular mechanisms underlying METH’s effects on EPC restoration of BBB integrity in the presence of HIV viral proteins ex vivo (Aim 2). The findings from this highly significant and clinically relevant exploratory project will shift the focus from METH’s damaging effects on the endothelial cell lining to METH’s detrimental actions on endothelial cell recovery, particularly with regard to the repair and restoration of a compromised BBB as a result of HIV infection.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$33,732 )
2024	2019	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Drug Use and Addiction Research Programs	000	2	10/11/2023	NON-COMPETING CONTINUATION	-$33,732
														Subtotal = -$33,732

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Drug Use and Addiction Research Programs	000	2	4/1/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $190,061 )
2019	2019	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Drug Use and Addiction Research Programs	000	2	4/11/2019	NON-COMPETING CONTINUATION	$190,061
														Subtotal = $190,061

Issue Date FY: 2018 ( Subtotal = $227,007 )
2018	2018	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Drug Use and Addiction Research Programs	000	1	4/6/2018	NEW	$227,007
														Subtotal = $227,007

Grand Total All Awards = $383,336

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Methamphetamine actions on recovery of the BBB damage related to HIV

Award Number: R21DA043448

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2018

PERIOD OF PERFORMANCE END DATE: 04/30/2022

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