# M-SCORCH: Methamphetamine use disorder data generation center for Single Cell Opioid Responses in the Context of HIV

> **NIH NIH U01** · YALE UNIVERSITY · 2021 · $1,944,127

## Abstract

PROJECT SUMMARY
HIV and methamphetamine (MA) use are global health problems with devastating human and societal
consequences. HIV and methamphetamine use also produce independent and additive impairments in
neurocognition, and current clinical and basic science research suggest complex and currently inadequately
understood interactions between HIV and MA pathophysiologies. We therefore propose to conduct
comprehensive characterization, at the single cell/nuclear level, of human brain tissue and regionally specified
organoids derived from human induced pluripotent stem cells. For these single nuclear (sn)RNA-seq and
snATAC-seq analyses, we will sample 3 brain regions (prefrontal cortex, ventral striatum, and basolateral
amygdala) critical for the neurobiological response to MA use in 20 brains from each of two donor groups,
HIV+MA+ and HIV-MA+. These data generation efforts will complement ongoing efforts in these same brain
regions from HIV-MA- and HIV+MA- donors and allow us to elucidate differences in gene expression and key
biological pathways that occur in response to MA use, HIV, or the combination of the two. In addition, we will
assay brain cell types for HIV transcripts, allowing us to identify cellular reservoirs of HIV in donor brains.
These efforts will be aided by the use of human cortical organoid and medial ganglionic eminence organoid
cultures, which offer complex, region-matched model systems recapitulating in vivo-like cellular diversity and
microenvironments without potentially confounding factors including patient history, varying co-morbidities,
prolonged postmortem intervals, or tissue degradation. We will then apply cutting edge and novel data analysis
pipelines to integrate snRNA-seq and snATAC-seq data and identify cell population and gene expression
differences between cell clusters (i.e., putative cell types) in different conditions. These data will also be
integrated with external datasets from the SCORCH Consortium and other multi-omic data including genotype,
RNA-seq, HiC, ChIP-seq, and ATAC-seq data from both healthy subjects and subjects with HIV infection,
neurological disease, or a history of drug abuse. Finally, we will use multiplexed immunohistochemistry and
single molecular fluorescent in situ hybridization to validate the cell type specific expression and co-expression
of candidate genes, biological processes, and gene regulatory networks implicated in the etiology of HIV or MA
pathophysiology. All data generation protocols and data analysis tools will be made freely available to the
research community, and all data generated will be provided as both raw and processed resources. Taken
together, the proposed experiments will generate invaluable resources and offer new biological insights into
the human brain and its disorders.

## Key facts

- **NIH application ID:** 10220577
- **Project number:** 1U01DA053628-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Ya-Chi Ho
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,944,127
- **Award type:** 1
- **Project period:** 2021-05-15 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10220577

## Citation

> US National Institutes of Health, RePORTER application 10220577, M-SCORCH: Methamphetamine use disorder data generation center for Single Cell Opioid Responses in the Context of HIV (1U01DA053628-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10220577. Licensed CC0.

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