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Molecular mechanisms: Dysregulation of monoamine transporters by HIV-1 Tat and cocaine

Award Number: R01DA035714
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2013
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Molecular mechanisms: Dysregulation of monoamine transporters by HIV-1 Tat and cocaine - People living with HIV (PLWH) face a high risk of neurocognitive impairments in depression and experience higher levels of impulsivity. The lifetime prevalence of cognitive depression in PLWH is twice that of HIV seronegative individuals. Cocaine abuse has been shown to enhance the incidence of HIV-1 associated cognitive depression and exacerbate its severity. Prolonged exposure to HIV-1 viral proteins causes dysregulation of monoamine transmission despite the advent of combination antiretroviral therapies (cART), which has been implicated as a key factor in developing impulsivity, cognitive depression, and cocaine abuse among HIV positive population. Results from our previous funding cycles have demonstrated that in vivo expression of HIV-1 Tat protein dysregulates monoamine transmission by its allosteric interaction with dopamine (DA) transporter (DAT) and norepinephrine transporter (NET) in inducible Tat transgenic (iTat-tg) mice. Furthermore, our preliminary in vitro and in vivo studies demonstrate that the in vivo Tat expression increases serotonin (5-HT) release and decreases 5-HT uptake through serotonin transporter (SERT) in the midbrain of iTat-tg mice, however, EcoHIV infection decreases 5-HT release in the midbrain and SERT- mediated 5-HT uptake in hippocampus of humanized mice for chronic HIV infection. These findings suggest that HIV-1 viral proteins dysregulate monoamine homeostasis via inhibition of monoamine transporters, which may potentially increase vulnerability to developing impulsivity, cognitive depression, and cocaine abuse in HIV-infected individuals. Studying single Tat protein allow us to identify targets in the brain for Tat binding and develop therapeutic intervention for HIV-induced neurological damages. Indeed, a novel allosteric inhibitor of monoamine transporters, SRI-32743, attenuates not only Tat-inhibited DA transport via DAT but also 5-HT uptake via SERT, and alleviates Tat-potentiated cognitive impairments and depressive-like behaviors. We hypothesize that HIV-1 Tat, acting via the unique binding sites, perturbs the monoamine transporter regulatory network and exacerbates cocaine-induced pathophysiological changes in monoaminergic transmission, resulting in impulsivity and depressive-like behaviors in the context of NeuroHIV. Three specific aims are proposed in investigating this hypothesis: (1) through computational modeling and experimental validation, identify the recognition binding pockets on human SERT for Tat, cocaine, allosteric modulator and explore the potential interactions with Tat and cocaine, (2) characterize the pathophysiological role of the SERT in Tat- and cocaine-dysregulated monoaminergic transmission, and (3) perform the proof-of-concept studies using a pharmacological approach with chemical probes to establish their potential for therapeutic application in treating impulsivity and depression. Collectively, this proposal is anticipated to provide both new therapeutics and mechanistic insights into how HIV promotes dysregulation of monoamine transmission in the context of poor impulsivity control, cognitive depression, and cocaine abuse.


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 = $728,575 )
2025	2025	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Drug Use and Addiction Research Programs	003	12	7/1/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$728,575
2025	2024	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Drug Use and Addiction Research Programs	001	11	4/1/2025	COMPETING CONTINUATION	$155,781
2025	2024	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Drug Use and Addiction Research Programs	002	11	7/1/2025	COMPETING CONTINUATION	$0
2025	2022	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Drug Use and Addiction Research Programs	000	10	4/1/2025	NON-COMPETING CONTINUATION	-$155,781
														Subtotal = $728,575

Issue Date FY: 2024 ( Subtotal = $696,079 )
2024	2024	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Drug Use and Addiction Research Programs	002	11	7/1/2024	COMPETING CONTINUATION	$696,079
2024	2022	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST	COLUMBIA	SC	29208	RICHLAND	USA	Drug Use and Addiction Research Programs	001	10	6/24/2024	NON-COMPETING CONTINUATION	$0
2024	2022	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Drug Use and Addiction Research Programs	000	10	12/14/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $696,079

Issue Date FY: 2022 ( Subtotal = $515,165 )
2022	2022	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Drug Use and Addiction Research Programs	000	10	1/26/2022	NON-COMPETING CONTINUATION	$463,648
2022	2022	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Drug Use and Addiction Research Programs	001	10	3/21/2022	NON-COMPETING CONTINUATION	$51,517
														Subtotal = $515,165

Issue Date FY: 2021 ( Subtotal = $515,554 )
2021	2021	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Drug Use and Addiction Research Programs	000	9	2/5/2021	NON-COMPETING CONTINUATION	$515,554
														Subtotal = $515,554

Issue Date FY: 2020 ( Subtotal = $515,165 )
2020	2020	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Drug Use and Addiction Research Programs	000	8	1/27/2020	NON-COMPETING CONTINUATION	$515,165
														Subtotal = $515,165

Issue Date FY: 2019 ( Subtotal = $515,554 )
2019	2019	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Drug Use and Addiction Research Programs	000	7	1/28/2019	NON-COMPETING CONTINUATION	$515,554
														Subtotal = $515,554

Issue Date FY: 2018 ( Subtotal = $537,119 )
2018	2018	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Drug Use and Addiction Research Programs	002	6	9/22/2018	COMPETING CONTINUATION	$113,989
2018	2018	UNIVERSITY OF SOUTH CAROLINA	1400 WHEAT ST	COLUMBIA	SC	29210	RICHLAND	USA	Drug Use and Addiction Research Programs	000	6	2/15/2018	COMPETING CONTINUATION	$537,119
2018	2017	UNIVERSITY OF SOUTH CAROLINA	1600 HAMPTON ST # 414	COLUMBIA	SC	29208	RICHLAND	USA	Drug Use and Addiction Research Programs	001	5	9/22/2018	NON-COMPETING CONTINUATION	-$113,989
														Subtotal = $537,119

Issue Date FY: 2017 ( Subtotal = $366,597 )
2017	2017	UNIVERSITY OF SOUTH CAROLINA	1400 WHEAT ST	COLUMBIA	SC	29210	RICHLAND	USA	Drug Use and Addiction Research Programs	001	5	3/3/2017	NON-COMPETING CONTINUATION	$329,937
2017	2017	UNIVERSITY OF SOUTH CAROLINA	1400 WHEAT ST	COLUMBIA	SC	29210	RICHLAND	USA	Drug Use and Addiction Research Programs	002	5	5/22/2017	NON-COMPETING CONTINUATION	$36,660
2017	2015	UNIVERSITY OF SOUTH CAROLINA	1400 WHEAT ST	COLUMBIA	SC	29210	RICHLAND	USA	Drug Use and Addiction Research Programs	000	3	2/22/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $366,597

Issue Date FY: 2016 ( Subtotal = $362,798 )
2016	2016	UNIVERSITY OF SOUTH CAROLINA	516 1/2 SOUTH MAIN STREET	COLUMBIA	SC	29208	RICHLAND	USA	Drug Use and Addiction Research Programs	000	4	4/5/2016	EXTENSION WITH OR WITHOUT FUNDS	$362,798
														Subtotal = $362,798

Issue Date FY: 2015 ( Subtotal = $360,839 )
2015	2015	UNIVERSITY OF SOUTH CAROLINA	516 1/2 SOUTH MAIN STREET	COLUMBIA	SC	29208	RICHLAND	USA	Drug Use and Addiction Research Programs	000	3	3/17/2015	NON-COMPETING CONTINUATION	$360,839
														Subtotal = $360,839

Issue Date FY: 2014 ( Subtotal = $366,215 )
2014	2014	UNIVERSITY OF SOUTH CAROLINA	516 1/2 SOUTH MAIN STREET	COLUMBIA	SC	29208	RICHLAND	USA	Drug Use and Addiction Research Programs	000	2	3/27/2014	NON-COMPETING CONTINUATION	$366,215
														Subtotal = $366,215

Issue Date FY: 2013 ( Subtotal = $377,339 )
2013	2013	UNIVERSITY OF SOUTH CAROLINA	516 1/2 SOUTH MAIN STREET	COLUMBIA	SC	29208	RICHLAND	USA	Drug Use and Addiction Research Programs	000	1	6/26/2013	NEW	$377,339
														Subtotal = $377,339

Grand Total All Awards = $5,856,999

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Molecular mechanisms: Dysregulation of monoamine transporters by HIV-1 Tat and cocaine

Award Number: R01DA035714

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2013

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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