# Identification of regulatory mechanisms operating in rare pathogenic astrocyte subsets in multiple sclerosis with a novel genomic technology

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $573,422

## Abstract

ABSTRACT
Single-cell genomic, epigenomic, and transcriptomic technologies can identify unique cell subsets with important
physiologic roles; however, RNA or DNA signatures cannot always be linked to unique surface markers,
hampering the re-isolation of these cell subsets for in-depth analyses. Moreover, conventional single-cell
methods require sequencing prohibitively large numbers of cells to characterize rare subsets. Here we will
develop and apply SEARCH-seq, a high-throughput cytometry method that detects RNA or DNA markers with
single molecule sensitivity that allows the rapid isolation of target cells for in-depth transcriptomic, genomic, or
epigenomic analyses. We will use the method to study the regulatory mechanisms controlling an astrocyte
subpopulation characterized by an alternatively spliced XBP1 transcript, which promotes disease pathology in
multiple sclerosis (MS). This subpopulation also manifests in the pre-clinical mouse model of experimental
autoimmune encephalomyelitis (EAE). Using SEARCH-seq in combination with conditional knock-out mice, in
vivo CRISPR/Cas9-driven perturbation studies, and RNA-seq analyses of mouse EAE and human MS samples,
we will characterize the role of these cells and their interaction with the nuclear receptor NR3C2 and its
corepressor NCOR2 in limiting XBP1-driven pathogenic astrocyte responses. In summary, SEARCH-seq is a
novel, sensitive, and high throughput method to capture rare brain cell subsets that are difficult to study with
existing technology and may have therapeutically targetable mechanisms relevant to MS pathogenesis.

## Key facts

- **NIH application ID:** 10737509
- **Project number:** 1R01NS130876-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Adam R. Abate
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $573,422
- **Award type:** 1
- **Project period:** 2023-08-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10737509

## Citation

> US National Institutes of Health, RePORTER application 10737509, Identification of regulatory mechanisms operating in rare pathogenic astrocyte subsets in multiple sclerosis with a novel genomic technology (1R01NS130876-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10737509. Licensed CC0.

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