U01DA056003

Single Cell Transcriptomic and Epigenomic Changes During Chronic HIV Infection and Cocaine Self-Administration - Project Summary

This application is submitted in response to RFA-D-21-019: Single Cell Opioid Responses in the Context of HIV (SCORCH) Program Expansion: CNS Data Generation for Chronic Opioid, Methamphetamine, and/or Cocaine Exposures. We have assembled an outstanding team of investigators with world-class expertise in HIV virology, addiction neurobiology, and single cell transcriptomics. We will leverage state-of-the-art single-nuclei RNA sequencing (snRNA-seq) coupled to single-nuclei epigenetics (snATAC-seq) to define the transcriptional and epigenetic landscape of neuronal and non-neuronal cells in addiction-relevant brain cells of HIV-infected mice that compulsively self-administer cocaine.

In this manner, we will identify cell types and brain sites in which HIV and cocaine interact to exacerbate the negative impact of HIV infection on the brain and contribute to the persistence of cocaine use disorder in infected individuals. To facilitate this goal, we have developed an extended access intravenous cocaine self-administration procedure for mice that precipitates compulsive-like response for cocaine that is resistant to negative outcome (contingently delivered noxious foot shocks).

We will utilize EcoHIV, which is a modified HIV strain that can infect conventional immunocompetent mice. The Chromium Single Cell Multiome ATAC and Gene Expression Assay and Multiplexed Error-Robust Fluorescence In Situ Hybridization (MERFISH) will be used to identify cocaine and/or HIV-responsive cells in the brain with unprecedented cellular and spatial resolution. We will confirm our major findings using postmortem brain tissues from cocaine-experienced HIV-infected individuals.

Our goals will be accomplished through the following four specific aims. In Aim 1, we will characterize compulsive-like cocaine intake in control and HIV-infected mice and determine the impact of antiretroviral treatment (ART) on cocaine response in these mice. In Aim 2, we will use snRNA-seq and multiome assays to identify those cells that show the most robust transcriptional and epigenetic plasticity to cocaine consumption and HIV infection. In Aim 3, we will use MERFISH to confirm and validate our major snRNA-seq and multiome assay findings, and generate more refined spatially resolved maps of those cells most impacted by cocaine and/or HIV. In Aim 4, we will confirm our major findings using post-mortem human brain tissues.

This highly innovative, collaborative, and multidisciplinary program of research promises to yield fundamental new insights into disease-related interactions between HIV infection and cocaine use.

Allen 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]

Seattle, Washington 981094307 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 308% from $3,557,665 to $14,516,969.