Modeling drugs of abuse-HIV interactions using ipsc-derived human cerebral organoids
Active Project Grant Awarded Last action
- Award ID
- R01DA053801
- Recipient
-
Scripps Research Institute UEI PHZJFZ32NKH4
- Awarding agency
-
National Institute on Drug Abuse
National Institutes of Health, Department of Health and Human Services
- Obligated
- $9,295,368
Award facts
- Assistance listing
- 93.279 Drug Use and Addiction Research Programs
- Completion date 95% complete
- Originally
- Funding
-
- $8,424,221.00 Federal
- $871,147.00 Non-federal
- Place of performance
- La Jolla, CA 92037, USA
Award details come from USAspending.gov.
Description
- Abstract
- HIV-infected microglia release cytokines, chemokines and viral gene products, such as GP120 and TAT, that are toxic to neurons. In this proposal, we will use human induced pluripotent stem cells (ipscs) to generate cortical and dopaminergic neurons as well as microglia, which will be cultured as organoids to model HIV-drug abuse interactions in conjunction with in-depth genomic approaches and electrophysiology. We show electrophysiological results that demonstrate that the levels of differentiation of the neurons in our organoids are comparable to in vivo and EX vivo preparations and are among the best that can be found in the scientific literature. To identify candidate host regulators of HIV expression and mediators of HIV-induced tissue damage and disease progression, we will expose microglia-containing cerebral organoids to methamphetamine (meth), a stimulant, and morphine, an opiate, which are members of two of the classes of drugs of abuse that are more prevalent among people living with HIV/aids (plwha). Cerebral organoids will be exposed to toxic HIV products such as TAT, GP120, drugs of abuse and combination antiretroviral therapy (cart). In some experiments we will also incorporate ipsc-derived astrocytes into microglia-containing cerebral organoids to test the role of astrocytes in neuroprotection and neurodegeneration. We will carry out single-cell gene expression profiling of ipsc-derived organoids exposed to drugs of abuse, HIV products, and cart and we will employ an advanced systems biology strategy to generate testable mechanistic hypotheses on the pathogenesis of neurodegeneration and tissue damage in neurohiv (aim 1) and identify candidate regulators of the LTR promoter that may shed light on the regulation of latency and reactivation of the HIV provirus (aim 2). In preliminary studies, this computational experimental approach allowed US to identify candidate drivers of gene expression changes associated with neurohiv and neurodegenerative diseases, including alzheimer's disease and drug and alcohol abuse. These findings support the overarching hypothesis that dissection of the gene regulatory network of the central nervous system will pave the way for the identification of novel mechanistic hypotheses and druggable targets to improve neuropsychological functioning of plwha and substance abuse comorbidity.
Transactions
| Action | Federal | Non-federal | Date |
|---|---|---|---|
| Amendment | $0 | $0 | |
| Amendment | $903,048 | $0 | |
| Amendment | $453,841 | $0 | |
| Amendment | $903,048 | $0 | |
| Amendment | $903,048 | $0 | |
| Amendment | $888,324 | $0 | |
| Amendment | $888,324 | $0 | |
| Amendment | $871,147 | $0 | |
| Amendment | $871,147 | $0 | |
| Amendment | $871,147 | $0 | |
| Original award | $871,147 | $871,147 |
Show all 11
Subawards
| Subrecipient | Amount | Awarded |
|---|---|---|
| Vala Sciences Inc. | $150,000 |
Quick answers
Who received award R01DA053801?
R01DA053801 was awarded to Scripps Research Institute by National Institute on Drug Abuse (National Institutes of Health) on September 30, 2021.
How much is award R01DA053801 worth?
$9,295,368 has been obligated on R01DA053801: $8,424,221 in federal funding and $871,147 in non-federal funding.
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