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Coupling of Inflammasome Cascades and Aberrant Neural Oscillatory Dynamics in NeuroHIV

Award Number: R01DA059877
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Coupling of Inflammasome Cascades and Aberrant Neural Oscillatory Dynamics in NeuroHIV - Project Summary/Abstract Persons with HIV (PWH) remain at an elevated risk of developing cognitive impairments. Such impairments are the most common neurological complication of HIV disease, and research targeting these comorbidities is one of four overarching priorities identified by the Office of AIDS Research (NOT-OD-20-018). Recent neuroimaging studies have broadly shown that the milder impairments more frequently observed in virally suppressed PWH arise from multiple cortical circuits, which is a major paradigm shift from the putative subcortical origins of the severe cognitive impairments observed earlier in the epidemic. However, despite this progress, we still have a limited understanding of the molecular precursors and pathways that lead to dysfunction in these cortical circuits, and virtually no viable therapeutic options, with only limited potential avenues (e.g., cannabis) on the horizon. This proposal responds to RFA-DA-24-003, which calls for applications that “identify and characterize common and specific inflammasome pathways” activated by illicit drugs and HIV, quantify “the impact of inflammasome activation on cognition and behavior,” evaluate “inflammasome signatures … and their use as biomarkers of neuroinflammation in PWH and substance use disorders (SUD),” and determine the “structural and functional consequences of inflammasome activation in different anatomical brain regions under the influence of SUD and HIV.” The proposed project responds to this call with a large-scale, innovative, dynamic functional mapping and molecular markers study that leverages multiple recent discoveries to identify the role(s) of inflammasome activation in the mechanisms and overall pathways underlying HIV-related inflammation and cognitive decline, as well as the impact of regular cannabis use on these parameters in virally suppressed PWH. Specifically, Aim 1 examines whether the neural oscillations and circuitry serving working memory and attention are modulated by inflammasome activity and/or the mitochondrial redox environment, which builds on our work featured in PNAS and Brain, Behavior, and Immunity that the superoxide-sensitive mitochondrial redox environment differentially predicts cognitive performance and the underlying neural oscillations in controls and PWH. Aim 2 quantifies the impact of regular cannabis use on inflammasome activity and the mitochondrial redox environment and follows on the heels of our finding that mitochondrial function differentially modulates superoxide in PWH relative to controls, and that superoxide predicts neuroinflammatory levels and cognitive function. Finally, Aim 3 builds on our recent finding that cannabis suppresses the pathological spontaneous cortical activity that is observed in PWH, and is accentuated in cognitively impaired PWH, by identifying whether these cannabis-induced effects are mainly driven by normalization of the mitochondrial redox environment, inflammasome activation, or both. These recent, major scientific advances provide an ideal foundation to directly address the key objectives of this RFA through an innovative project that uses state-of-the-art neuroimaging and systems biology methods to build on an established model of neuroinflammation that has been linked to cognitive and neural dysfunction 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: 2026 ( Subtotal = $503,862 )
2026	2026	FATHER FLANAGAN'S BOYS' HOME	14100 CRAWFORD ST	BOYS TOWN	NE	68010	DOUGLAS	USA	Drug Use and Addiction Research Programs	000	3	1/29/2026	NON-COMPETING CONTINUATION	$503,862
														Subtotal = $503,862

Issue Date FY: 2025 ( Subtotal = $559,846 )
2025	2025	FATHER FLANAGAN'S BOYS' HOME	14100 CRAWFORD ST	BOYS TOWN	NE	68010	DOUGLAS	USA	Drug Use and Addiction Research Programs	000	2	12/16/2024	NON-COMPETING CONTINUATION	$503,862
2025	2025	FATHER FLANAGAN'S BOYS' HOME	14100 CRAWFORD ST	BOYS TOWN	NE	68010	DOUGLAS	USA	Drug Use and Addiction Research Programs	001	2	4/21/2025	NON-COMPETING CONTINUATION	$55,984
														Subtotal = $559,846

Issue Date FY: 2024 ( Subtotal = $574,278 )
2024	2024	FATHER FLANAGAN'S BOYS' HOME	14100 CRAWFORD ST	BOYS TOWN	NE	68010	DOUGLAS	USA	Drug Use and Addiction Research Programs	000	1	3/11/2024	NEW	$574,278
														Subtotal = $574,278

Grand Total All Awards = $1,637,986

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Coupling of Inflammasome Cascades and Aberrant Neural Oscillatory Dynamics in NeuroHIV

Award Number: R01DA059877

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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