# Single Cell Transcriptomics of the Cocaine Use Disorder in the Context of HIV

> **NIH NIH U01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $1,527,174

## Abstract

PROJECT SUMMARY
Systemic immune activation in people living with HIV has been hypothesized to account for higher incidence of
chronic inflammatory diseases, including HIV-associated neurocognitive disorders (HAND). Acute HIV infection
in the CNS is thought to initiate a cascade of pro-inflammatory events that result in inflammation-induced
neuronal injury and associated neurocognitive disorders that are evident even in the present combination
antiretroviral therapy (cART) era. The use of psychostimulants (such as cocaine and methamphetamine) and
alcohol has been shown to disrupt BBB integrity. Disrupted BBB may increase immune cell infiltrating into the
CNS and promote glial activation, increased inflammation and neurotoxicity. Interestingly, increased permeability
of BBB has been implicated in the progression of HIV neurological dysfunction. Thus, the combined effect of
cocaine usage and HIV infection can cause an additive effect on BBB disruption and further impact HIV-related
neurocognitive impairments. However, not much genome-wide molecular level study has been done in
understanding BBB integrity in substance use disorder and in HIV infection/HAND. The proposed study will
address this important question. Our central hypothesis is that cocaine misuse exacerbates HIV pathogenesis
in the CNS by disrupting blood-brain barrier and dysregulating the glial population in the brain. Our overall
objective is to exploit cell type specific transcriptomic information at the single nuclei level from patient brain
samples to characterize the effects of cocaine use disorder on CNS neuronal and glial cells, HIV infection and
HANDs. We will characterize single nuclei gene expression and identify dysregulated gene regulatory networks
in each of the neuronal and glial populations associated with cocaine misuse in HIV infected individuals and/or
with HANDs. We will also perform computational analysis to identify neuronal and glial cell regulatory networks
altered by cocaine misuse. In the validation and functional characterization component, we will characterize top
genes in 3D brain organoid model and will characterize with CRISPR knockout and overexpression of the gene.
Successful completion of these aims will have significant research and clinical impact by 1) elucidating how
cocaine misuse alters HIV/HAND pathogenesis in the CNS, and 2) discovering candidate molecules to regulate
HIV infection or persistence in the CNS in the context of cocaine misuse.

## Key facts

- **NIH application ID:** 10644020
- **Project number:** 5U01DA056006-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Christine Cheng
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,527,174
- **Award type:** 5
- **Project period:** 2022-06-15 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10644020

## Citation

> US National Institutes of Health, RePORTER application 10644020, Single Cell Transcriptomics of the Cocaine Use Disorder in the Context of HIV (5U01DA056006-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10644020. Licensed CC0.

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