# Pathogenic fibroblast differentiation in rheumatoid arthritis

> **NIH NIH K08** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $168,669

## Abstract

Project Summary/Abstract:
This proposal details a five-year research and training plan with a scientific focus on defining the role of Notch
signaling in driving pathogenic synovial fibroblast expansion in joints of patients with rheumatoid arthritis.
The candidate spearheaded high-dimensional profiling studies of RA synovia that identified expansion of
pathological sublining fibroblasts in RA (Mizoguchi, Slowikowski, Wei et al., Nature Communications, 2018
and Zhang*, Wei*, Slowikowski*, Fonseka*, Rao et al, Nature Immunology, 2019). The PI recently
discovered that Notch signaling is a key regulator of pathogenic sublining fibroblasts differentiation. The long-
term objective of the proposed study is to define how Notch signaling regulate pathological functions that
contribute to RA pathology and determine if Notch receptors can be therapeutically targeted to treat arthritis.
The specific aims proposed here utilize three complementary approaches to define how Notch regulates
synovial fibroblast differentiation and function in RA. Aim 1 will identify Notch receptors critical for fibroblast
differentiation towards a sublining fibroblast phenotype. Aim 2 interrogates the impact of global and fibroblast-
specific Notch inactivation on synovitis in a mouse model of inflammatory arthritis. Aim 3 examines
transcriptional control of Notch-driven fibroblast pathology.
Using a combination of single cell technology, patient-derived tissues, and mouse model of arthritis, this study
will provide the candidate with new training in bioinformatics, gene editing, and transgenic mouse model. The
candidate’s immediate career development goals are to acquire expertise in bioinformatics and computational
biology to guide analysis of single cell RNAseq data. A specific career development plan tailored to the
candidate’s training needs is described by both the candidate and the mentors: Dr. Michael Brenner MD, an
expert in fibroblast biology and rheumatoid arthritis, and Dr. Soumya Raychaudhuri MD PhD, an expert in
single cell bioinformatics.
The PI is an MD/PhD rheumatologist whose long-term goal is to become a tenure-track faculty focusing on
developing novel treatments for rheumatic diseases. The proposed studies, training plan, and exceptional
environment at Brigham and Women’s Hospital and Harvard Medical School will pave the way for the PI’s
transition to an independent investigator and a leader in arthritis research.

## Key facts

- **NIH application ID:** 9948908
- **Project number:** 1K08AR077037-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Kevin S Wei
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $168,669
- **Award type:** 1
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948908

## Citation

> US National Institutes of Health, RePORTER application 9948908, Pathogenic fibroblast differentiation in rheumatoid arthritis (1K08AR077037-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9948908. Licensed CC0.

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