The goal of this proposal is to identify citrullinated biomarkers of cancer, rheumatoid arthritis and colitis. This goal will be achieved by developing a highly practical and versatile technology to detect and characterize citrullinated proteins in complex proteomes. Protein citrullination is increased in virtually all inflammatory diseases, as well as cancer, and the evidence indicates that this post-translational modification is a major contributor to disease pathogenesis. In fact, inhibition of protein citrullination decreases diseas severity in animal models of rheumatoid arthritis, ulcerative colitis, nerve damage, and cancer. Thus, citrullinated biomarkers most likely exist and exploiting these citrullination events for disease diagnostics presents a single provocative strategy that is applicable to multiple diseases. The approach proposed herein is innovative because a new paradigm is being tested - that citrullinated proteins are disease biomarkers. Additionally, an enabling technology will be developed that can be used to identify citrullinated biomarkers in numerous disease states. The platform being developed is faster and more versatile than existing technologies, providing a unique strategy to interrogate the role of citrullination in these diseases. Furthermore, this technology can be extended to the identification and quantification of citrullinated proteins by MS, which is not possible with existing technologies. This new platform is therefore not only applicable to screening patient samples to identify biomarkers, but can be adapted to enrich and identify specific citrullinated proteins, thereby providing deeper insight into the functional roleof citrullination. This technology, coupled with the disease models and collaborator expertise in this grant, enables the exploration of a potential paradigm-shifting outcome, whereby the detection of citrullination events provides a common diagnostic for a multitude of divergent diseases. The impact of this proposal is multifold. First, the identification of citrullinated biomarkers will alow for better, more tailored treatments, because they can be used to diagnose and monitor the efficacy of treatments for these diseases. Second, these efforts will define the 'citrullinome', thereby facilitating a greater understanding of how this modification contributes to normal and pathological processes. Third, these findings will determine if there is a common link between these disparate diseases. In summary, the funding of this proposal will ultimately provide powerful chemical probes for scientists interested in the in vivo role of protein citrullination an will have a strong translational impact on the development of diagnostics and therapeutics for numerous diseases.

Public Health Relevance

The identification of disease biomarkers has been identified by the NIH as a high priority research area. Such biomarkers can be used to diagnose and monitor the efficacy of therapeutic interventions. The citrullinated protein biomarkers that we plan to identify will be useful for diagnosing and monitoring the progression of a variety of inflammatory diseases and cancers.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fabian, Miles
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Massachusetts Medical School Worcester
Schools of Medicine
United States
Zip Code
Tilvawala, Ronak; Nguyen, Son Hong; Maurais, Aaron J et al. (2018) The Rheumatoid Arthritis-Associated Citrullinome. Cell Chem Biol 25:691-704.e6
Carmona-Rivera, Carmelo; Carlucci, Philip M; Moore, Erica et al. (2017) Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis. Sci Immunol 2:
Muth, Aaron; Subramanian, Venkataraman; Beaumont, Edward et al. (2017) Development of a Selective Inhibitor of Protein Arginine Deiminase 2. J Med Chem 60:3198-3211
Sun, Bo; Dwivedi, Nishant; Bechtel, Tyler J et al. (2017) Citrullination of NF-?B p65 promotes its nuclear localization and TLR-induced expression of IL-1? and TNF?. Sci Immunol 2:
Young, Coleman H; Rothfuss, Heather M; Gard, Philip F et al. (2017) Citrullination regulates the expression of insulin-like growth factor-binding protein 1 (IGFBP1) in ovine uterine luminal epithelial cells. Reproduction 153:1-10
Clancy, Kathleen W; Russell, Anna-Maria; Subramanian, Venkataraman et al. (2017) Citrullination/Methylation Crosstalk on Histone H3 Regulates ER-Target Gene Transcription. ACS Chem Biol 12:1691-1702
Clancy, Kathleen W; Weerapana, Eranthie; Thompson, Paul R (2016) Detection and identification of protein citrullination in complex biological systems. Curr Opin Chem Biol 30:1-6
Kawalkowska, Joanna; Quirke, Anne-Marie; Ghari, Fatemeh et al. (2016) Abrogation of collagen-induced arthritis by a peptidyl arginine deiminase inhibitor is associated with modulation of T cell-mediated immune responses. Sci Rep 6:26430
Bawadekar, Mandar; Gendron-Fitzpatrick, Annette; Rebernick, Ryan et al. (2016) Tumor necrosis factor alpha, citrullination, and peptidylarginine deiminase 4 in lung and joint inflammation. Arthritis Res Ther 18:173
Chang, Hui-Hsin; Liu, Guang-Yaw; Dwivedi, Nishant et al. (2016) A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22. JCI Insight 1:e90045

Showing the most recent 10 out of 21 publications