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Immunomodulation of nicotine in HIV-1Tg rat brain

Award Number: R01DA046258
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: 03/31/2025

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Immunomodulation of nicotine in HIV-1Tg rat brain - Project Summary: As one of the key active ingredients of tobacco smoke, nicotine exerts its actions primarily on the nicotinic acetylcholine receptors (nAChRs), which are expressed on neurons, microglia, and other cells in the central nervous system (CNS). Activation of nAChRs by nicotine has various potential therapeutic immune benefits, including modulation of inflammatory responses, maintenance of immune homeostasis, and regulation of expression of pro- and anti-inflammatory factors. However, smokers have a higher rate of HIV disease progression and behavioral and cognitive complications, with differences seen between male and female smokers. It has been suggested that prolonged exposure to nicotine in HIV patients through cigarette smoking might decrease the expression and desensitize the activation of nAChRs, which could dampen nicotine's ability to mediate immune responses. During the past several years, we have conducted a series of behavioral and molecular studies using a rodent HIV-1 transgenic (HIV-1Tg) rat model to study various medical issues, including immunity, associated with HIV patients receiving combined anti-retroviral therapy (cART). We used this HIV-transgenic rat model to determine the effects of nicotine on brain function in the presence of HIV-1 proteins and found that chronic treatment with nicotine can restore the expression of many genes altered by the HIV-1 viral proteins in signaling pathways involved in immunity and other neuronal systems. In addition, we found that expression of various nAChR subunits, especially α6, β3, and β4, and immune-related genes, such as interferon regulatory factor 7 (IRF7) and interleukin-1α (IL-1α), differ greatly in HIV-1Tg rats compared with F344 controls. Our findings indicate that HIV-1 proteins greatly impact CNS immunity as well as nAChR function and alter the responsiveness to nicotine in certain immune-related and nAChR-mediated signaling pathways. Based on these findings, we hypothesize that there are significant interactions between nicotine and HIV-1 proteins that affect the immune response to nicotine in the brain of HIV-1-positive individuals. To test this hypothesis, we propose the following three aims. Aim 1 is to determine the interactive effects of nicotine and HIV viral proteins on microglia and macrophages in the brain as well as cytokine production in the blood and brain of the HIV-1Tg rat. Aim 2 is to compare the interactive effects of nicotine and HIV-1 viral proteins on gene expression in three brain regions of male and female HIV-1Tg rats using RNA-seq analysis. Aim 3 is to characterize specific genes and pathways that mediate the effects of the interaction between nicotine and HIV- 1 viral proteins using various molecular techniques, including CRISPR gene editing. The proposed studies represent the first application of next-generation sequencing technique in combination with conventional molecular approaches to investigate the modulatory effects of chronic use of nicotine on CNS immunity in the presence of HIV-1 viral proteins. By combining both genomic and molecular approaches, our studies will be comprehensive and free of subjective bias and assure the value of the data for the development of new strategies for treating HIV-1 patients who use nicotine.


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 = -$170,885 )
2025	2022	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Drug Use and Addiction Research Programs	000	5	8/11/2025	NON-COMPETING CONTINUATION	-$170,885
														Subtotal = -$170,885

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Drug Use and Addiction Research Programs	000	5	8/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $347,750 )
2022	2022	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Drug Use and Addiction Research Programs	000	5	3/22/2022	NON-COMPETING CONTINUATION	$347,750
														Subtotal = $347,750

Issue Date FY: 2021 ( Subtotal = $347,750 )
2021	2021	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Drug Use and Addiction Research Programs	000	4	3/26/2021	NON-COMPETING CONTINUATION	$347,750
														Subtotal = $347,750

Issue Date FY: 2020 ( Subtotal = $347,750 )
2020	2020	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Drug Use and Addiction Research Programs	000	3	3/26/2020	NON-COMPETING CONTINUATION	$347,750
														Subtotal = $347,750

Issue Date FY: 2019 ( Subtotal = $347,750 )
2019	2019	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Drug Use and Addiction Research Programs	000	2	3/20/2019	NON-COMPETING CONTINUATION	$347,750
														Subtotal = $347,750

Issue Date FY: 2018 ( Subtotal = $347,750 )
2018	2018	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Drug Use and Addiction Research Programs	001	1	9/26/2018	NEW	$0
2018	2018	SETON HALL UNIVERSITY	400 S ORANGE AVE	SOUTH ORANGE	NJ	07079	ESSEX	USA	Drug Use and Addiction Research Programs	000	1	4/27/2018	NEW	$347,750
														Subtotal = $347,750

Grand Total All Awards = $1,567,865

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Immunomodulation of nicotine in HIV-1Tg rat brain

Award Number: R01DA046258

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: 03/31/2025

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