Charles Warwick

Mentor: Yuriy M. Usachev, PhD

Year Entered Into Program: 2012

PhD Institution: University of Iowa, 2017

Affiliations

  • Pharmacology

Research Description

The role of the complement system, specifically C3a and C5a, in mediating chronic pain states using calcium imaging to examine the sensitization of nociceptors through complement activation.

The complement system is a principal component of innate immunity. It consists of more than 30 proteins that are rapidly recruited through a cascade of enzymatic reactions to contribute to host defenses through diverse mechanisms. In spite of growing evidence implicating the complement system in the development of pain hypersensitivity, the underlying mechanisms are still not understood. ¬¬My research focuses on elucidating functions of the complement system in initiating and maintaining chronic pain and to determine the underlying mechanisms. I hypothesize that complement fragments C3a and C5a produce hypersensitivity in pain sensing neurons called nociceptors by facilitating TRPV1 (noxious heat receptor) function via both direct and indirect pathways. The direct pathway involves functional coupling of C3a/C5a receptors with TRPV1 in Dorsal Root Ganglia (DRG) neurons and recruits the PLC-PKC-TRPV1 signaling downstream of C3a/C5a receptor activation. The indirect pathway involves C3a/C5a-dependent activation of immune cells (most likely macrophages), release of NGF, and NGF/TrkA-dependent potentiation of TRPV1. This research will increase our understanding of how the immune system contributes to the pathogenesis of pain triggered by injury or illness. In particular, by exploring previously unrecognized signaling pathways involving C3aR, C5aR, and TRPV1, it will help to identify novel mechanisms that underlie nociceptor sensitization by the complement system and may lead to the development of new analgesics targeting complement fragments and their receptors.

Publication(s)

  1. Warwick CA, Usachev YM.:  Culture, Transfection, and Immunocytochemical Analysis of Primary Macrophages. Methods Mol Biol 1554:161-173, 2017.  PMID: 28185189
  2. Shutov LP*, Warwick CA*, Shi X, Gnanasekaran A, Shepherd AJ, Mohapatra DP, Woodruff TM, Clark JD and Usachev YM. The Complement System Component C5a Produces Thermal Hyperalgesia via Macrophage-to-Nociceptor Signaling that Requires NGF and TRPV1. J Neurosci 36(18):5055-70, 2016.  PMCID: PMC4854968  *Co-authors

Books/Chapters

  1. Warwick, CA and Usachev, YM "Culture, Transfection and Immunocytochemical Analysis of Primary Macrophages." Signal Transduction Immunohistochemistry: Methods and Protocols. 2nd ed. New York, NY: Humana, 2017. 161-173. Print.  PMID: 28185189

Award(s)

  • Diabetes Research Training Program, 2017-present
  • Pharmaceutical Research & Manufacturers of America Foundation (PhRMA) Award, 2016-2017 
  • NIH Fellowship appointment of Interdisciplinary Training in Pain Research (NIH T32 NS045549), University of Iowa, 2015-2016
  • Fellowship appointment of NIH Training Grant in Pharmacological Sciences (NIH T32 GM067795), University of Iowa, 2014-2015
  • Institutional fellowship support of Training Grant in Pharmacological Sciences (NIH T32 GM067795), University of Iowa, 2013-2014
  • Graduate Student Senate Travel Award, 2013-2016
  • Executive Council of Graduate & Professional Students Travel Award, 2013

 Abstract(s)

  1. C.A. Warwick, L.P. Shutov, S.R. White, X. Shi,   J.D. Clark,  D.L. Hammond and Y.M. Usachev. Mechanisms of complement C5a-induced mechanical sensitization in mouse: The roles of macrophages, cytokines and TRPV1. Society for Neuroscience 2015. Poster presentation
  2. L.P. Shutov, C.A. Warwick, J.D. Clark, and Y.M. Usachev. Complement C5a produces macrophage dependent nociceptive sensitization via TRPV1 in mouse. University of Iowa Research Day 2014. Poster presentation 
  3. L.P. Shutov, C.A. Warwick, J.D. Clark, and Y.M. Usachev. Complement C5a produces macrophage dependent nociceptive sensitization via TRPV1 in mouse. Society for Neuroscience 2014. Poster presentation
  4. L.P. Shutov, C.A. Warwick, J.D. Clark, and Y.M. Usachev. Complement C5a produces nociceptive sensitization via TRPV1 in mouse. Society for Neuroscience 2013. Poster presentation

Awards since graduating the U of IA

  • Postdoctoral Fellowship on the Training in Mechanisms and Clinical Presentation of Pain, (T32 NS073548), NIH/NINDS, University of Pittsburgh, 2018-present

 

Research