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Oligodendrocyte damage and dysfunction in HIV associated neurocognitive disorder

Award Number: R01MH098742
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/16/2012
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Oligodendrocyte damage and dysfunction in HIV associated neurocognitive disorder - Despite effective viral control by Antiretroviral therapy (ART), HIV associated neurocognitive disorder (HAND)persists in 30-50% of people with HIV (PWH). The pathology of HAND includes white matter (WM) changes such as decreased myelin sheath thickness, myelin lesions, and abnormal myelin protein expression. We have found that both HIV infection and a subset of antiretroviral drugs disrupt oligodendrocyte (OL) maturation and myelination. These data support our overarching hypothesis that HIV infection and select ART compounds attenuate OL differentiation and myelin formation, contributing to CNS dysfunction in persons with HIV (PWH) on ART. Our in vitro data on the effects of HIV and ART drugs on OL differentiation align with in vivo evidence for a prominent role of the integrated stress response (ISR) and lipid metabolism in ART drug- and HIV-induced changes in WM. Transcriptome studies reported significant induction of transcripts indicative of activation of the ISR and unfolded protein response coincident with significant decrease in transcripts encoding regulators of lipid metabolism and specific myelin proteins in WM from PWH on ART. We have reported that a subset of ART drugs and a model of HIV infection induce the ISR, particularly the Protein kinase R-Endoplasmic Reticulum Kinase (PERK), in OLs. Our preliminary data demonstrate altered levels of lipid metabolism enzymes and lipids in response to ART drugs. Both processes correlate with inhibition of OL differentiation. Numerous studies have demonstrated that ISR kinase PERK regulates lipid metabolism; however, the role of ISR/PERK-induced stress granule (SG) formation, which are membraneless organelles containing mRNAs that protect a subset of transcripts during ISR activation, has not been investigated. Our preliminary data demonstrate the presence of SGs in OLs in WM of PWH with HAND and in OLs exposed to ART drugs in vitro. These findings have led us to hypothesize that HIV infection and a subset of ART compounds induce the ISR leading to stress granule formation and disruption of lipid metabolism in OL, causing defects in differentiation and myelin formation in PWH, contributing to CNS dysfunction. To address this hypothesis: aim 1 will determine whether HIV or select ART drugs cause the ISR-induced formation of SGs, which mRNAs critical for myelination are sequestered in SGs, and whether SGs are toxic to the cell. These goals will be pursued in our well-tested in vitro model of oligodendrocyte differentiation, in a small animal model and in samples from PWH. In aim 2, we will determine how both HIV and select ART drugs alter lipid composition and lipid regulation in OLs, also employing our in vitro model, a small animal model and samples from PWH. We will also determine the impact of ISR on lipid regulation and composition in this system. Finally, in specific aim 3, we will determine if neuroimaging-based measures of WM health associates with genetic variants of PERK and lipid metabolism in the context of functional subdomains of cognitive and mental health changes in PWH.


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: 2025 ( Subtotal = $635,229 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	12	12/16/2024	NON-COMPETING CONTINUATION	$635,229
														Subtotal = $635,229

Issue Date FY: 2024 ( Subtotal = $870,237 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	005	11	9/13/2024	COMPETING CONTINUATION	$83,898
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	11	12/18/2023	COMPETING CONTINUATION	$702,439
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	004	11	5/14/2024	COMPETING CONTINUATION	$0
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	002	11	5/6/2024	COMPETING CONTINUATION	$83,900
2024	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	003	10	5/14/2024	NON-COMPETING CONTINUATION	$0
2024	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	001	10	2/9/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $870,237

Issue Date FY: 2022 ( Subtotal = $792,002 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	001	10	5/12/2022	NON-COMPETING CONTINUATION	$68,164
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	10	12/22/2021	NON-COMPETING CONTINUATION	$613,471
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	002	10	8/19/2022	SUPPLEMENT FOR EXPANSION	$110,367
														Subtotal = $792,002

Issue Date FY: 2021 ( Subtotal = $681,323 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	002	9	5/11/2021	NON-COMPETING CONTINUATION	$68,132
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	001	9	12/15/2020	NON-COMPETING CONTINUATION	$613,191
2021	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	8	11/11/2020	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $681,323

Issue Date FY: 2020 ( Subtotal = $1,103,519 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	001	8	3/11/2020	NON-COMPETING CONTINUATION	$68,102
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	8	12/24/2019	NON-COMPETING CONTINUATION	$612,917
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	002	8	8/17/2020	SUPPLEMENT FOR EXPANSION	$422,500
														Subtotal = $1,103,519

Issue Date FY: 2019 ( Subtotal = $680,724 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	7	12/22/2018	NON-COMPETING CONTINUATION	$680,724
														Subtotal = $680,724

Issue Date FY: 2018 ( Subtotal = $710,938 )
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	002	6	7/11/2018	COMPETING CONTINUATION	$3,119
2018	2018	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	6	3/23/2018	COMPETING CONTINUATION	$710,938
2018	2016	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	001	5	7/11/2018	EXTENSION WITH OR WITHOUT FUNDS	-$3,119
														Subtotal = $710,938

Issue Date FY: 2016 ( Subtotal = $532,571 )
2016	2016	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	5	3/25/2016	EXTENSION WITH OR WITHOUT FUNDS	$532,571
														Subtotal = $532,571

Issue Date FY: 2015 ( Subtotal = $532,571 )
2015	2015	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	4	6/9/2015	NON-COMPETING CONTINUATION	$532,571
														Subtotal = $532,571

Issue Date FY: 2014 ( Subtotal = $532,571 )
2014	2014	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	3	6/25/2014	NON-COMPETING CONTINUATION	$532,571
														Subtotal = $532,571

Issue Date FY: 2013 ( Subtotal = $511,268 )
2013	2013	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	2	7/9/2013	NON-COMPETING CONTINUATION	$511,268
														Subtotal = $511,268

Issue Date FY: 2012 ( Subtotal = $547,571 )
2012	2012	UNIVERSITY OF PENNSYLVANIA	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Mental Health Research Grants	000	1	7/16/2012	NEW	$547,571
														Subtotal = $547,571

Grand Total All Awards = $8,130,524

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Oligodendrocyte damage and dysfunction in HIV associated neurocognitive disorder

Award Number: R01MH098742

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/16/2012

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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