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Investigating the molecular mechanisms of HIV/AIDS associated neurological disorders using microglia and cerebral organoids derived from induced pluripotent stem cells

Award Number: R01DA049524
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY High prevalence of HIV-associated neurocognitive disorders (HAND) poses a major challenge for the society. While there is evidence that both HIV-1 and methamphetamine can cause behavioral, neurocognitive and histopathological changes in the brain, and affect immune defense, the combined effect and potential interaction of both the virus and the drug remains incompletely understood. In addition, fundamental and critical questions regarding how HIV- infects microglia to establish latent infection and infected microglia alter neural tissue structure, physiology, and function in brain remain to be addressed. The overall objective of this proposal is to delineate the molecular and cellular mechanisms by which HIV infection alters the function of microglia, resident immune cells of the brain, and CNS that leads to neuronal injury and pathogenesis of HAND. Recent advances in embryonic stem cell and induced pluripotent stem cells (iPSCs) technologies have opened up new avenues of disease modeling in vitro. We put forward an unprecedented concept and experimental system to model human microglia-brain interactions as well as opportunities to illuminate how genetic variation affects gene expression. Our project has three specific aims: Specific Aim 1: Establish iPSC-derived cerebral organoids and define the cellular diversity, neural tissue structure, physiology, and gene expression programs. Specific Aim 2: Determine how HIV infection alters microglia and CNS during HIV neuropathogenesis. Specific Aim 3: Determine the molecular mechanisms of neuronal injury by HIV. Our results will be corroborated with gene expression programs using single nuclei of microglia and neurons obtained from postmortem tissues of HAND patients. Gene targets of HAND risk variants activity in disease-relevant cell types will be determined. Further, we will validate our findings in human brain tissues through the National NeuroAIDS Tissue Consortium (NNTC) and SIV infected brains of rhesus monkeys. Results of these studies will provide fundamental understanding of the molecular mechanisms that are altered by HIV and methamphetamine use leading to immune and brain dysfunctions.


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: 2023 ( Subtotal = $782,711 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Drug Abuse and Addiction Research Programs	000	5	7/31/2023	NON-COMPETING CONTINUATION	$782,711
														Subtotal = $782,711

Issue Date FY: 2022 ( Subtotal = $782,711 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Drug Abuse and Addiction Research Programs	000	4	7/28/2022	NON-COMPETING CONTINUATION	$782,711
														Subtotal = $782,711

Issue Date FY: 2021 ( Subtotal = $782,711 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Drug Abuse and Addiction Research Programs	000	3	7/14/2021	NON-COMPETING CONTINUATION	$782,711
														Subtotal = $782,711

Issue Date FY: 2020 ( Subtotal = $780,441 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Drug Abuse and Addiction Research Programs	000	2	7/21/2020	NON-COMPETING CONTINUATION	$780,441
														Subtotal = $780,441

Issue Date FY: 2019 ( Subtotal = $780,235 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Drug Abuse and Addiction Research Programs	000	1	7/3/2019	NEW	$780,235
														Subtotal = $780,235

Grand Total All Awards = $3,908,809

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Investigating the molecular mechanisms of HIV/AIDS associated neurological disorders using microglia and cerebral organoids derived from induced pluripotent stem cells

Award Number: R01DA049524

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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