To establish a Data Center to coordinate and analyze single cell and other molecular data sets generated by Single Cell Opioid Responses in the Context of HIV (SCORCH) and other NIDA-funded HIV and substance use disorder projects and to make the data findable, accessible, interoperable, and reusable (FAIR) to enable secondary analyses by the scientific community. This is a non-competitive funding opportunity intended to fund a single award. The National Institute on Drug Abuse (NIDA) is announcing its intent to issue a single source cooperative agreement award to the University of Maryland Baltimore to 1. Coordinate all the data generated by the SCORCH consortium, 2. Analyze all the data generated by the SCORCH consortium, 3. Perform necessary SCORCH program scientific outreach activities, and 4. Support SCORCH consortium communication. The current SCORCH Data Center is integrated with the rest of the SCORCH consortium and is familiar with the current data, metadata, and data quality metric standards and data pipelines. They were involved in establishing these standards and have been/are working closely with key personnel on SCORCH data generation projects to ensure data and associated metadata are deposited. Continued support of the University of Maryland Baltimore SCORCH Data Center to complete the SCORCH Program activities will enable seamless SCORCH data coordination and archiving, will prevent disruption in data analysis, and will allow continued support of the currently existing SCORCH website which is the scientific face of the SCORCH program.

Background

Single Nucleus Assays: Molecular analysis of brain tissue typically relies on ensemble averaging of heterogenous mixtures of cell types within a specific brain region. However, 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 nucleus assay for transposase-accessible chromatin-sequencing (snATAC-seq), single cell Hi-C, and spatial genomics approaches such as multiplexed fluorescence in situ hybridization (FISH). Individual researchers as well as large project teams including the Human Cell Atlas, Common Fund Human BioMolecular Atlas Program (HuBMAP), and NIH BRAIN Initiative Cell Atlas Network (BICAN) 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.

Addictive Substances. Chronic exposure to addictive substances 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 exposures to addictive substances influence the states and functions of these cells.

HIV/ART. Antiretroviral therapy (ART) 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 [HAND]). Use of addictive substances by HIV-infected individuals has the potential to further alter immune function and/or exacerbate HIV-related CNS impairment. However, little is known about 1. The effects of persistent HIV infection or HIV treatment regimens on gene expression in specific CNS cell types in key brain regions, or 2. How chronic addictive substance use might modify these effects.

SCORCH. The Single Cell Opioid Responses in the Context of HIV (SCORCH) consortium was formed to begin to address scientific questions about addiction and HIV/ART questions at the single cell level. Fifteen funded SCORCH data generation projects (NIDA SCORCH Program) have been generating brain snRNA-seq or snATAC-seq data. Four brain types are being assayed by all groups: control, drug-exposed/SUD, HIV+, and HIV+drug exposed/SUD. Emphasis is on individuals with chronic exposure to opioids, cocaine, methamphetamine, or cannabinoids. Four groups are generating data from non-human primate brain, four from rodent brain, and nine from human post-mortem brain with some data from human organoids as well. The SCORCH data coordination, analysis, and scientific outreach center was established to standardize and share the single cell molecular HIV/SUD data generated by this program by ensuring that the data is FAIR (Findable, Accessible, Interoperable, and Reusable). Harmonized molecular and single cell HIV/SUD data sets will enable data mining by the scientific community to uncover new HIV and/or SUD mechanisms and to identify candidate pathways for therapeutic intervention. The SCORCH Data Center will also enable future mining of these data sets as improved data science and information technology approaches are developed, maximizing NIDA ’s original investment in the data generating activities.

Scope. The proposed project should be framed to answer one or more vexing questions about persistent HIV infection in the brain. In addition, the major thrust of the proposed project MUST:

Propose to coordinate and analyze single cell and other molecular data sets generated by SCORCH and other NIDA-funded HIV and substance use disorder projects.
Propose to make this data findable, accessible, interoperable, and reusable (FAIR) to enable secondary analyses by the scientific community.
Applicants are encouraged to contact NIDA program staff to answer any questions. Key activities of the SCORCH Data Center will be to:

Work with SCORCH consortium members to ensure that all data and metadata have standardized formats and associated quality metrics and have been processed through standardized pipelines.
Associate new SCORCH data with clinical metadata from the appropriate brain banks or tissue sources.
Work closely with the SCORCH consortium PD(s)/PI(s) to analyze the data generated, to develop analysis strategies to integrate the datasets in synergistic ways with other relevant datasets, and to share useful information and insights about these data with the broader biomedical research community. It is anticipated that the SCORCH Data Center will lead an integrative analysis of all the SCORCH single cell data in a capstone publication.
Develop strategies to enable and improve coordination, analysis, and sharing of spatial genomics and related data types.
Develop strategies to enable and improve coordination, analysis, and sharing of data types from spatially and/or functionally resolved cellular assemblies relevant to HIV or addiction. Examples include but are not limited to anatomical structures, functional networks and ensembles characterized under PAR-20-241/ RFA-DA-22-011/ RFA-DA-23-035 “Large Scale Integrated Mapping and Molecular Profiling of Cell Ensembles and/or Cell-Types Mediating Opioid Action in the Rodent Brain” and RFA-DA-23-036 “Investigating the Effects of Addictive Substances on Brain Developmental Trajectories Using Innovative Scalable Methods for Quantification of Cell Identity, Lineage and Connectivity.”
Archive raw and processed datasets generated by the SCORCH consortium in appropriate NIH-supported archives.
Maintain, and improve a website to serve as a community-wide nexus for SCORCH protocols, assay and data standards, raw and processed data, data pipelines, and other resources generated by the consortium.
Facilitate SCORCH data use by the scientific community for data mining to identify candidates for SUD and/or HIV therapeutic targets or to investigate SUD or HIV mechanisms. Provide user-friendly access to consortium data and by identifying or generating robust tools to enable both naive and experienced investigators to query, integrate, analyze, and model the data.
Develop workshops and implement a community outreach strategy to inform the research community of the accomplishments of the SCORCH program and disseminate information about the community resources and data generated by the program.
Coordinate SCORCH consortium activities by organizing steering committee meetings, workgroup meetings, external program consultant logistics, and other awardee meetings as needed.
Plan for Enhancing Diverse Perspectives :

This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP) as described in NOT-MH-21-310, submitted as Other Project Information as an attachment (see Section IV).
Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance material. The PEDP will be assessed as part of the scientific and technical peer review evaluation, as well as considered among programmatic matters with respect to funding decisions.