# Project #1 Pascual

> **NIH NIH P50** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $646,551

## Abstract

SLE is clinically complex and molecularly heterogeneous. While monogenic cases are identified, a
complex genetic background involving mutations in regulatory regions plus environmental factors are at the core
of the more common, sporadic SLE cases. Project 1 builds upon our long-term approaches to address critical
gaps in understanding SLE molecular heterogeneity, which might contribute to phase 3 clinical trial failures.
During the previous cycle of this CORT, we used PBMC bulk and single cell transcriptional and epigenetic studies
to further understand the origin and composition of the major SLE blood signatures. These studies revealed that
i) the IFN signature is restricted to a few major cellular clusters and minor subclusters within PBMCs, ii) unique
subsets of myeloid cells co-express IFN-Stimulated Genes (ISGs) and IL-1, and iii) the expression of monogenic
lupus-related genes preferentially maps to DCs and B cells/Plasmablasts. In addition, we confirmed that
transcriptional signals associated to the erythroid lineage represent a biomarker of DA in a subset of pediatric
SLE patients. To ascertain the involvement of erythroid cells in SLE pathogenesis, we have now developed in
vitro systems that recapitulate human erythropoiesis starting with PBMCs. These studies have unraveled a novel
pathogenic loop involving mature red blood cells that retain mitochondria (Mito+ RBCs), opsonizing anti-RBCs
autoantibodies and myeloid cell activation in SLE.
 We now propose to further develop these studies in order to decode both i) upstream signals and ii)
downstream events related with the presence of Mito+ RBCs with the ultimate goal of identify novel targets for
therapy and/or DA biomarkers. In Aim 1, we will identify the ultimate upstream mechanisms leading to
mitochondrial removal during healthy erythropoiesis and how these mechanisms become dysfunctional in
erythroid progenitors from SLE patients. As part of this Aim, we will also follow the presence of Mito+ RBCs and
the upstream dysfunctional pathways that give rise to them in pediatric and adult SLE patients during flares and
remissions, and will establish their correlation with SLE molecular subgroups, anti-RBCs autoantibodies and
other auto-specificities as well as clinical phenotypes. Our data support that Mito+ RBCs contribute to both, IFN
and inflammasome activation upon opsonization and internalization within myeloid cells. In Aim 2, we will dissect
the downstream pro-inflammatory pathways induced by Mito+ RBCs in PBMCs and in selected purified cell
populations, especially professional phagocytes. This project will benefit from our well-characterized pediatric
cohort, resources developed through the past 15 years to study the human immune system, and an exclusive
group of collaborators and advisors complementing our expertise. Successful completion of Project 1 will i)
elucidate upstream alterations leading to a unique SLE erythroid lineage dysfunction, ii) unravel novel pathways
contribut...

## Key facts

- **NIH application ID:** 10404366
- **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:** $646,551
- **Award type:** 2
- **Project period:** 2016-09-21 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10404366

## Citation

> US National Institutes of Health, RePORTER application 10404366, Project #1 Pascual (2P50AR070594-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10404366. Licensed CC0.

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