To support generation of single cell RNA-sequencing data sets for at least one brain region relevant to persistent HIV infection and opioid, cocaine and/or methamphetamine use disorder.
Molecular analysis of brain tissue typically relies on ensemble averaging of heterogenous mixtures of cell types within a specific brain region. However recent technological advances enable molecular characterization of large numbers of individual cells. Single cell approaches can uncover effects on rarer cell types and have the potential to reveal cellular differences resulting from specific niche environments or transitory cellular states. Some single cell technologies in use include single cell RNA-sequencing (scRNA-seq), single nucleus RNA-sequencing (snRNA-seq), single cell ATAC-seq, single cell Hi-C, and spatial genomics approaches such as multiplexed FISH. Individual researchers as well as large project teams including the Human Cell Atlas, Common Fund HuBMAP, and NIH BRAIN Initiative Cell Census Network (BICCN) are exploiting these technologies to understand the diversity of cell types within the human body as well as their functions in human health and disease.
Chronic exposure to opioids, methamphetamine, and/or cocaine can lead to long term changes in brain function and to substance use disorders (SUDs). Many known brain regions are involved in addictive processes including the prefrontal cortex, nucleus accumbens, ventral tegmental area, striatum, insula, amygdala, and hippocampus. Despite great advances in our understanding of molecular pathways and circuits involved in SUDs, there remains limited knowledge concerning 1. the specific types, numbers, and gene expression profiles of cells within these brain regions and 2. how environmental exposures to addictive substances influence the states and functions of these cells.
Antiretroviral therapy has, in large part, transformed the HIV epidemic into a chronic manageable disease in the United States. However, people living with HIV remain at higher risk for impaired cognitive functions (e.g. HIV-Associated Neurocognitive Disorder or HAND). Use of addictive substances by HIV-infected individuals has the potential to further diminish immune function and/or exacerbate HIV-related CNS impairment. However, little is known about 1. the molecular characteristics of CNS cell types that might preferentially harbor HIV, 2. the effects of persistent HIV infection or HIV treatment regimens on specific CNS cell types in key brain regions, or 3. how chronic addictive substance use might modify these effects. Single cell technologies have the potential to shed light on these processes.
This FOA (and the previously issued RFA-DA-19-037) aims to support projects proposing to generate single cell or single nucleus RNA-sequencing data sets for at least one brain region relevant to persistent HIV infection and SUDs. If fully successful, this project will 1. establish gene expression differences in cell types within this brain region differ from one another, potentially enabling cell type-specific genetic or pharmacological manipulation, 2. reveal the molecular effects of HIV infection/treatment in the CNS, providing potential targets for manipulation of HIV persistence and/or HIV neurobiological sequelae, 3. uncover cell type-specific gene expression changes resulting from chronic opioid, cocaine, and/or methamphetamine exposure providing potential novel therapeutic targets for addiction, and 4. identify potential synergistic effects of chronic addictive substance exposure and HIV infection in the CNS.
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