# Project 1: Understanding the molecular pathways in SLE pathogenesis

> **NIH NIH P50** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $610,602

## Abstract

Program Director/Principal Investigator (Last, First, Middle): PD: Pascual, V. / PI: Project 1 Pascual, V. 
Project Summary 
Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by widespread inflammation 
and development of autoantibodies against nuclear antigens. SLE is clinically heterogeneous and molecularly 
diverse. This heterogeneity might contribute to the high occurrence of clinical trial failures, underscoring the 
need for biomarkers to stratify patients according to individual pathogenic drivers of disease. In an attempt to 
understand the complexity of SLE, we established a pediatric cohort and have followed it for the past decade 
using validated clinical disease activity (DA) measures as well as blood gene expression profiles during flares 
and remissions. Our studies confirm the prevalence of IFN, neutrophil/myeloid and plasmablast gene 
signatures and their correlation with DA at the cohort level. Personalized immunomonitoring revealed, 
however, significant heterogeneity in how these major signatures correlate with DA at the individual patient 
level. We hypothesize that decoding the cellular and/or molecular components of these signatures in well- 
defined groups of patients will enable development of biomarkers and computational tools for stratification, 
which will enable rational clinical trial design. 
Towards this goal, we are proposing two aims: 1) to establish the origin and composition of three major 
SLE blood signatures at the single cell level. We will examine the cells that give rise to these signatures 
using high definition immunophenotyping and transcriptional profiling at the population and single cell levels; 2) 
to determine if molecular DA markers correlate with altered cytosolic and/or endosomal nucleic acid 
(NA) sensing pathways in ex vivo patient blood cells and in vitro assays. Here, we first propose to apply 
a sensitive and robust assay to quantify the endogenous activity of cGAS, a universal cytosolic DNA sensor, in 
PBMCs from patients during flares and remissions. Second, we will test the response of patient cells to 
relevant endosomal and cytosolic nucleic acid ligands in vitro using multi-dimensional readouts. Through the 
implementation of our aims, we will i) reveal the source of SLE molecular signatures; ii) understand the extent 
of heterogeneity of blood SLE myeloid cells and plasma cells; iii) determine which cell subsets/molecular 
pathways and/or NA sensors contribute to immune activation leading to SLE flares. Understanding SLE 
heterogeneity and developing tools to assess it in the clinical setting will ultimately open new paths towards 
personalized therapeutic approaches.

## Key facts

- **NIH application ID:** 10155422
- **Project number:** 5P50AR070594-05
- **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:** 2021
- **Award amount:** $610,602
- **Award type:** 5
- **Project period:** 2016-09-21 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10155422

## Citation

> US National Institutes of Health, RePORTER application 10155422, Project 1: Understanding the molecular pathways in SLE pathogenesis (5P50AR070594-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10155422. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*