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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM110394-01
Application #
8672286
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Fabian, Miles
Project Start
2014-05-01
Project End
2014-07-31
Budget Start
2014-05-01
Budget End
2014-07-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Scripps Florida
Department
Type
DUNS #
City
Jupiter
State
FL
Country
United States
Zip Code
33458
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
Fuhrmann, Jakob; Thompson, Paul R (2016) Protein Arginine Methylation and Citrullination in Epigenetic Regulation. ACS Chem Biol 11:654-68
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
Fuhrmann, Jakob; Subramanian, Venkataraman; Kojetin, Douglas J et al. (2016) Activity-Based Profiling Reveals a Regulatory Link between Oxidative Stress and Protein Arginine Phosphorylation. Cell Chem Biol 23:967-977
Fuhrmann, Jakob; Clancy, Kathleen W; Thompson, Paul R (2015) Chemical biology of protein arginine modifications in epigenetic regulation. Chem Rev 115:5413-61
Witalison, Erin E; Thompson, Paul R; Hofseth, Lorne J (2015) Protein Arginine Deiminases and Associated Citrullination: Physiological Functions and Diseases Associated with Dysregulation. Curr Drug Targets 16:700-10
Witalison, Erin E; Cui, Xiangli; Causey, Corey P et al. (2015) Molecular targeting of protein arginine deiminases to suppress colitis and prevent colon cancer. Oncotarget 6:36053-62
Lewallen, Daniel M; Bicker, Kevin L; Subramanian, Venkataraman et al. (2015) Chemical Proteomic Platform To Identify Citrullinated Proteins. ACS Chem Biol 10:2520-8
Subramanian, Venkataraman; Knight, Jason S; Parelkar, Sangram et al. (2015) Design, synthesis, and biological evaluation of tetrazole analogs of Cl-amidine as protein arginine deiminase inhibitors. J Med Chem 58:1337-44
Slade, Daniel J; Horibata, Sachi; Coonrod, Scott A et al. (2014) A novel role for protein arginine deiminase 4 in pluripotency: the emerging role of citrullinated histone H1 in cellular programming. Bioessays 36:736-40

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