U01DA056006

Single Cell Transcriptomics of the Cocaine Use Disorder in the Context of HIV - Project Summary

Systemic immune activation in people living with HIV has been hypothesized to account for a higher incidence of chronic inflammatory diseases, including HIV-associated neurocognitive disorders (HAND). Acute HIV infection in the central nervous system (CNS) is thought to initiate a cascade of pro-inflammatory events that result in inflammation-induced neuronal injury and associated neurocognitive disorders, which 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 blood-brain barrier (BBB) integrity. Disrupted BBB may increase immune cell infiltration 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 the 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 HAND.

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 HAND. 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 a 3D brain organoid model and will characterize them 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.

San Diego University Of California

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 920930689 United States

Single Zip Code

Single Cell Opioid Responses in the Context of HIV (SCORCH) Program Expansion: CNS Data Generation for Chronic Opioid, Methamphetamine, and/or Cocaine Exposures (U01 Clinical Trial Not Allowed) (RFA-DA-21-019)

Amendment Since initial award the total obligations have increased 301% from $1,561,951 to $6,266,450.