Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects millions of people worldwide. Disease progression includes inflammation of the synovium, a membrane that encapsulates the joint and contains the synovial fluid. The synovium, composed mostly of fibroblasts, is central to disease pathogenesis in RA. It forms an invasive tissue called pannus that recruits immune cells such as T cells and B cells, destroys articular cartilage in the joint, and mediates signaling leading to activation of bone-resorbing osteoclasts. In this project, we will study synovial fibroblasts obtained from fresh tissue discarded during joint replacement surgery. Our work will define the cellular population structure of fibroblasts in the synovium by assaying single-cell gene expression profiles. In RA, the synovium has a heterogeneous mixture of signaling molecules and cell types that influence a positive feedback loop between the tissue and the cells of the immune system. This project aims to define a detailed transcriptional network synergistically activated by tumor necrosis factor (TNF) and interleukin 17 (IL17A). This work will establish basic knowledge about the transcriptional functions of synovial fibroblasts, so it may have broad implications for RA and other diseases that are mediated by fibroblasts in connective tissues such as psoriasis and interstitial pneumonia.

Public Health Relevance

Rheumatoid arthritis is a debilitating inflammatory disease affecting millions of individuals worldwide wherein the synovium, a membrane encapsulating the joint, is central to disease pathogenesis. The cellular composition and molecular functions of fibroblast cells in the synovium are relevant to understanding disease, and this project aims to determine the distinct functions of cellular populations of the synovium and reveal gene networks activated by cytokines elevated in the disease state. This work may reveal fibroblast-specific targets for the treatment of inflammatory diseases mediated by fibroblasts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AR070582-02
Application #
9337242
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mao, Su-Yau
Project Start
2016-09-01
Project End
2018-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Biology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115