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.
This study aims to examine differentiation of pathological synovial fibroblasts in the joints of patients with rheumatoid arthritis. We identified Notch signaling as a novel regulator of synovial fibroblast differentiation. Understanding how Notch signaling regulates synovial fibroblasts function may provide new therapeutic strategies to block pathological fibroblast differentiation by targeting Notch signaling.