# Project #2 - Banchereau

> **NIH NIH P50** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $639,003

## Abstract

PROJECT SUMMARY PROJECT 2
SLE has high morbidity and limited treatment options. ~30% of patients fail to respond to the standard-of-care
(SOC) treatment, composed of hydroxychloroquine (HCQ), Glucocorticoids (GCs), and mycophenolate mofetil
(MMF). Another ~30% of patients initially respond with a decreased activity index (SLEDAI) and a decrease in
plasmablasts (PBs), but subsequently become refractory to treatment. The biological mechanisms that underlie
this lack of response to treatment are poorly understood. Thus, to progress towards improved clinical
management of SLE especially in the ~60% of SLE patients who currently do not have effective treatment options
in the long term, the goal of Project 2 is to delineate the mechanisms of resistance to SOC therapy and to identify
novel targets for therapeutic intervention. In the previous CORT funding cycle, we focused on characterizing the
transcriptomes of peripheral blood mononuclear cells (PBMCs) from a cross-sectional pediatric SLE patient
cohort using single-cell (sc) RNAseq and long-read (LR) sequencing technologies. We found that multiple cell
types -- monocytes, dendritic cells, plasma cells (PCs), and subsets of CD4+ and CD8+ T cells -- exhibit an
interferon (IFN) signature. LRseq uncovered >250 isoforms unique to SLE, which include several cell surface
molecules with immune regulatory functions. Preliminary data from 11 patients from a longitudinal cohort showed
that a high SLEDAI at diagnosis correlates with elevated numbers of PBs. Importantly, transcriptional profiling of
pre-therapy samples suggested that the PBs of non-responder (NR) patients are distinct from those of responder
(R) patients, including increased expression of IFN-stimulated genes (ISGs) in R-PBs. Finally, we have used
bulk and single-nucleus (sn) ATAC-seq to identify epigenomic signatures of SLE. Here, we will combine single-
cell approaches in an expanded longitudinal cohort with functional genomics to uncover treatment resistance
pathways in SLE and novel therapeutic targets. In Aim 1, we will identify SOC resistance pathways at the single-
cell transcriptional level using blood samples collected longitudinally from 30 SLE patients identified at the onset
of disease and followed over at least 3 years. We will uncover transcriptional signatures of therapy resistance
by performing Total-seq and identify isoforms associated with disease severity and response to treatment. In
Aim 2, we will uncover epigenomic signatures and regulatory elements associated with SLE and therapy
resistance using single-nucleus ATACseq and link these to transcriptional programs identified in Aim 1.
Longitudinal samples are essential for determining whether disease-specific genomic signatures change upon
treatment and/or during flares. In Aim 3, we will characterize the phenotype of therapy-resistant PBs and apply
CRISPR-Cas9 functional genomics approaches to validate candidate molecules that confer resistance to
therapy. Successful completi...

## Key facts

- **NIH application ID:** 10404367
- **Project number:** 2P50AR070594-06
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Maria Virginia Pascual
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $639,003
- **Award type:** 2
- **Project period:** 2016-09-21 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404367

## Citation

> US National Institutes of Health, RePORTER application 10404367, Project #2 - Banchereau (2P50AR070594-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10404367. Licensed CC0.

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