U01DA058527

Elucidating Single Cell Changes in Neurogenic Brain Regions during HIV and Cannabinoid Exposure - Project Summary (Abstract)

The use of cannabis for recreation and medicinal purposes is disproportionately high among people living with HIV (PLWH), and nearly half of cannabis-using PLWH are estimated to be at risk for cannabis use disorder. Yet, whether cannabis is therapeutic or detrimental on the central nervous system (CNS) of PLWH remains controversial, highlighting the need for well-controlled studies generating reproducible data from specific cannabinoids, brain regions, and CNS cell types.

Our research has shown that cell-type specific epigenetic patterns relate to HIV-associated cognitive impairment in PLWH. Additionally, more frequent or recent cannabis use may reduce myeloid inflammation and impact brain structure in PLWH. Furthermore, our recent single cell studies of the CNS in PLWH revealed distinct cerebrospinal fluid (CSF) microglia-like cells expressing CD204 in PLWH and ongoing HIV viral transcription in CSF cells despite antiretroviral therapy (ART).

Prior research has shown that neurogenic brain regions, including the subventricular zone of the lateral ventricles and hippocampus, are of high relevance to persistent HIV infection and cannabinoid exposures. However, critical gaps in understanding neurogenic brain regions at the single cell level in the setting of HIV and cannabinoid exposures remain.

We are leveraging brain tissues from an established oral dosing model of cannabidiol (CBD) and THC in a nonhuman primate (NHP) model of HIV. The application of new single cell technologies, permitting the simultaneous profiling of gene expression and open chromatin from the same cell (10x Genomics Multiome: RNA+ATAC), in brain tissues, along with a new single cell assay capable of measuring multiple histone modifications, and pharmacological profiling of current ART regimens and cannabinoid levels in brain tissues.

Our central hypothesis is a therapeutic role of cannabinoids in ameliorating HIV neuropathogenesis in the CNS by enhancing the proliferation and survival of neural progenitor cells and immature neurons and reducing glial inflammation. To identify cell types, epigenetic cell states, and gene pathways relevant to neuropathogenesis, viral persistence, and cannabinoid exposures, we are harnessing 180 brain tissue samples from an established oral administration of either CBD or THC in NHP and single cell assays (10x Genomics Single Nucleus Multiome and a new single cell assay developed at the NYGC capable of measuring the genome-wide presence of multiple histone modifications and protein-DNA binding sites).

Moreover, accompanying single cell data will be generated from conserved neurogenic brain regions of human postmortem brain tissues from 40 donors based on HIV status (+/-) and cannabis exposure (+/-). We will also explore the frequency of single cells in neurogenic regions of the brain that are infected and impacted by cannabinoids by harnessing a bioinformatics pipeline that detects both viral transcripts and transposase accessible provirus.

This project will generate comprehensive single cell datasets in NHP and humans to improve our understanding of the cross talk between HIV and cannabinoids in neurogenic regions of the brain and has high programmatic priority to goals of the SCORCH program expansion.

Weill Medical College Of Cornell University

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]

New York, New York 100654805 United States

Single Zip Code

Single Cell Opioid Responses in the Context of HIV (SCORCH) Program Expansion: CNS Data Generation for Chronic Opioid, Methamphetamine, Cocaine and/or Cannabinoid Exposures (U01 - Clinical Trial Not Allowed) (RFA-DA-23-004)

Amendment Since initial award the total obligations have increased 180% from $2,531,125 to $7,084,951.