R01DA053801

Modeling Drugs of Abuse-HIV Interactions Using iPSC-Derived Human Cerebral Organoids - Summary

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. We will also utilize in-depth genomic approaches and electrophysiology. Our organoids have shown electrophysiological results that demonstrate the comparable levels of differentiation of the neurons to in vivo and ex vivo preparations, making them among the best 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. These drugs are members of two classes of drugs of abuse that are more prevalent among people living with HIV/AIDS (PLWHA). Additionally, 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. Using an advanced systems biology strategy, we aim to generate testable mechanistic hypotheses on the pathogenesis of neurodegeneration and tissue damage in neuroHIV (Aim 1). Furthermore, we will identify candidate regulators of the LTR promoter that may shed light on the regulation of latency and reactivation of the HIV provirus (Aim 2). Preliminary studies using this computational experimental approach have 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.

Scripps Research Institute

TO SUPPORT BASIC AND CLINICAL NEUROSCIENCE, BIOMEDICAL, BEHAVIORAL AND SOCIAL SCIENCE, EPIDEMIOLOGIC, HEALTH SERVICES AND HEALTH DISPARITY RESEARCH. TO DEVELOP NEW KNOWLEDGE AND APPROACHES RELATED TO THE PREVENTION, DIAGNOSIS, TREATMENT, ETIOLOGY, AND CONSEQUENCES OF DRUG ABUSE AND ADDICTION, INCLUDING HIV/AIDS. TO SUPPORT RESEARCH TRAINING AND RESEARCH SCIENTIST DEVELOPMENT. TO SUPPORT DISSEMINATION OF RESEARCH FINDINGS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) LEGISLATION IS INTENDED TO EXPAND AND IMPROVE THE SBIR PROGRAMS TO EMPHASIZE AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF TECHNOLOGY DEVELOPED THROUGH FEDERAL SBIR RESEARCH AND DEVELOPMENT, INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN THE SBIR PROGRAM. THE LEGISLATION INTENDS THAT THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.279 - Drug Abuse and Addiction Research Programs

National Institute on Drug Abuse (NIDA) [HHS - NIH]

La Jolla, California 920371000 United States

Single Zip Code

Advancing Exceptional Research on HIV/AIDS and Substance Abuse (R01, Clinical Trial Optional) (RFA-DA-18-022)

Amendment Since initial award the total obligations have increased 461% from $871,147 to $4,890,555.