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Function of astrocytes autophagy in brain homeostasis and opioid-induced maladaptive behavior and addiction, in the context of HIV

Award Number: R01DA057884
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Function of astrocytes autophagy in brain homeostasis and opioid-induced maladaptive behavior and addiction, in the context of HIV - SUMMARY/ABSTRACT The overarching goal of this proposal is to identify and characterize mechanistic pathways in astrocytes responsible for changes in drug-evoked structural and synaptic plasticity that underlie the maladaptive behavior in opioid drug abuse. Astrocytes are a logical focus for these studies, as they are intimately involved in diverse neuronal function, including modulation of synaptic function and plasticity, regulating concentrations of the excitatory neurotransmitter glutamate, and yet secrete and response to neuroinflammatory cytokines, chemokines, and growth factors. These processes are themselves regulated by autophagy: the process by which cells both engage in orderly degradation and recycling of cellular components as well as balancing energy metabolism. Although astrocyte-mediated excitation and inflammation have been implicated in neuroadaptations and drug-seeking behavior, the role of astrocytes autophagy in the mechanism underlying the intersection between the glutamate system and neuroimmune signaling, is not well understood. Findings from our lab showed that a key autophagy protein, Beclin1, is strongly associated with the secretion of cytokines, chemokines, and growth factors released from glia and neurons. We also showed that activation of autophagy increases glutamate uptake along with glutamate transporters expressed in astrocytes, collectively establishing a strong premise for the current proposed investigations. Extending our initial studies, here we hypothesize that autophagy- mediated neuroimmune signaling and glutamate metabolism in astrocytes ± HIV alters neuronal circuitry to promote opioid use disorder (OUD) and abuse. Since opioid and HIV-infection are common comorbidities, and opioids are commonly prescribed to HIV-infected individuals experiencing pain, studies will include assessment of HIV-infection through use of EcoHIV in a series of mouse models, facilitating the needed behavioral, neuroanatomical, and mechanistic studies to address the current knowledge gap. In Specific Aim (SA) 1 we will use Becn1+/- and Becn1+/+ mice to define the role of astrocyte autophagy with or without HIV and/or chronic opioid exposure on the progression and magnitude of opioid addiction, withdrawal, long-term abstinence, and relapse in validated behavioral models. In SA 2 we will use brain tissue harvested from mice tested in Aim 1 to decipher the interlink between excitation and inflammation-evoked changes in neurochemical and neuroanatomical plasticity and maladaptive behavior in opioid drug abuse (with or without HIV), through the lens of astrocytes autophagy. In SA 3 we will use brain cells to further investigate the mechanisms by which Beclin1 interacts with the μ-opioid receptor and/or associated proteins and analyze how Beclin1 activity modulates endolysosomal trafficking and degradation of MOR intracellular trafficking in brain cells in response to opioid (with and without HIV). Findings are expected to produce mechanistic insights into how autophagy regulates the underlying crosstalk between astrocytes and neuronal circuitry mediating OUD and abuse behaviors, yielding both novel therapeutic targets for development and strategies for preventing OUD in at risk HIV populations.


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 = $349,157 )
2026	2026	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	000	4	3/24/2026	NON-COMPETING CONTINUATION	$349,157
														Subtotal = $349,157

Issue Date FY: 2025 ( Subtotal = $349,323 )
2025	2025	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	001	3	4/11/2025	NON-COMPETING CONTINUATION	$34,932
2025	2025	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	000	3	3/17/2025	NON-COMPETING CONTINUATION	$314,391
														Subtotal = $349,323

Issue Date FY: 2024 ( Subtotal = $349,424 )
2024	2024	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	001	2	4/26/2024	NON-COMPETING CONTINUATION	$34,942
2024	2024	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	000	2	3/20/2024	NON-COMPETING CONTINUATION	$314,482
														Subtotal = $349,424

Issue Date FY: 2023 ( Subtotal = $360,823 )
2023	2023	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	000	1	5/12/2023	NEW	$360,823
														Subtotal = $360,823

Grand Total All Awards = $1,408,727

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Function of astrocytes autophagy in brain homeostasis and opioid-induced maladaptive behavior and addiction, in the context of HIV

Award Number: R01DA057884

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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