Skip Navigation
 

Department of Oral Health Sciences

Dr. KeithL. Kirkwood


KeithL. Kirkwood, DDS, PhD
Associate Dean for Research
Professor and Chair, Department of Oral Health Sciences
Professor, Department of Microbiology and Immunology
 
Director, Center for Oral Health Research

Contact Information
klkirk@musc.edu
230-A BSB
173 Ashley Ave.
Charleston, SC 29425
Phone: 843-792-0969
Fax: 843-792-6626


Education:
B.A., West Virginia University
D.D.S., West Virginia University
Ph.D., State University of New York at Buffalo
Certificate (Periodontology), State University of New York at Buffalo
Post Doctoral Fellowship (Molecular Biology), State University of New York at Buffalo

Honors and Awards:
Young Investigator Award, University at Buffalo
Tarrson Fellowship Career Development Award, AAP Foundation
ADR/GSK Innovation in Oral Care Award

Department Affiliations:
Craniofacial Biology, CDM
Microbiology and Immunology, COM

Research Interests:

The production of inflammatory cytokines is a tightly controlled process that involves both transcriptional and posttranscriptional mechanisms.  In stimulated cells, maximal induction of cytokine expression requires activation of the p38 MAPK/MK2 stress kinase pathway. Our group is focused on understanding how the p38/MK2 cell-signaling pathway regulates inflammatory cytokine expression in the context of osteoclastogenesis and inflammatory bone loss.  Specifically we interested in p38 MAPK signaling that regulates many cytokine genes at the posttranscriptional level.  In one funded study, we are addressing RNA-binding proteins regulate IL-6 mRNA expression and contribute towards alveolar bone loss through posttranscriptional regulation of innate immune cytokines. 

Inactivation of MAPKs is achieved mainly by a family of dual-specific MAPK phosphatases (MKPs) that target the regulatory sites of these kinases. MKP-1 is the founding member of this class of phosphatases capable of dephosphorylating MAPK activity to attenuate the innate immune inflammatory cytokine response. Recent evidence from acute inflammatory models suggests that MKP-1 contributes towards LPS tolerance and over-expression of MKP-1 accelerates p38 inactivation resulting in diminished proinflammatory cytokine production.  In a related study, the role of p38/MKP-1 signaling in chronic inflammation (i.e. periodontal diseases) has been initiated over the past few years. 

We have established small animal models of periodontal disease where periodontal pathogenic LPS can induce significant bone loss.  Using this model, we have evaluated the potential of p38 MAPK small molecule inhibitors to prevent or attenuate LPS-induced periodontal bone loss.  Recent funding related to these studies is focused on using small interfering RNA to block p38 and MK2 in periodontal disease progression.

Other areas of recent focus have recently been established in the field of oral cancer.  Along with other investigators, models of oral cancer in nude mice have been established to help us understand the role of tumor-derived cytokine and matrix metalloproteinase expression that may be important for oral cancer local invasion into bone.  Roles of MKP-1 and RNA binding proteins in oral cancer progression are also being pursued at the present time.
 
Recent Publications:

1.  Rossa, Jr., C., K. Ehmann, C. Patil, and K. L. Kirkwood.  MKK3/6-p38 MAPK    
     Signaling Is Required For IL-1β Induced RANKL Expression in Bone Marrow
     Stromal Cells.  Journal of Interferon and Cytokine Research, 26:719-729, 2006.
2.  Patil, C., C. Rossa, Jr., and K. L. Kirkwood.  A. actinomycetemcomitans LPS
     Induces IL-6 Expression through Multiple MAPK Pathways in Periodontal 
     Ligament Fibroblasts.  Oral Microbiology and Immunology, 21:392-98, 2006.
3.  Kirkwood, K.L., J.Cirelli, J. Rogers, and W. V. Giannobile.  Novel Host Response
    Therapeutic Approaches to Treat Periodontal Diseases, Perio 2000, 40: 294-315,
    2007.
4. Henson, B., F. Li, D.D. Coatney, T.E. Carey, R.S. Mitra, K.L. Kirkwood, and N.J.
    D’Silva. An orthotopic floor-of mouth model for loco-regional growth and spread of 
    human squamous cell carcinoma. Journal of Oral Pathology and Medicine, J Oral 
    Pathol Med. 36(6):363-70, 2007
5. Kirkwood, K.L., F. Li, J. E. Rogers, J. Otremba, D.D. Coatney, J.M. Kreider, N.J.
    D’Silva, S. Chakravarty, S.Dugar, A. A. Protter, and S. Medicherla.  A p38a
    Selective Mitogen Activated Protein Kinase Inhibitor Prevents Periodontal Bone
    Loss.  Journal of Pharmacology and Experimental Therapeutics 320(1); 56-63,
    2007.
6. Rogers, J.E., F. Li, D.D. Coatney, C. Rossa, Jr., P. Bronson, J. Kriegl, W.V. 
    Giannobile, and K. L. Kirkwood. Actinobacillus actinomycetemcomitans LPS-
    Mediated Experimental Bone Loss Model for Aggressive Periodontitis. J.
    Periodontology, 78:550-558, 2007. 
7. Rossa, Jr., C., M. Liu, K. L. Kirkwood. A dominant function of p38 Mitogen
    Activated Protein Kinase signaling in Receptor Activator of Nuclear Factor-κB
    Ligand expression and osteoclastogenesis induction by A.
    actinomycetemcomitans and E. coli LPS.  J Periodontal Research, 43(2): 201-11,
    2007.
8. Rogers J.E., S. Medicherla, F. Li , D.D. Coatney, J. Otremba , J. Kriegl , A. 
    Protter, L.S. Higgins, and Kirkwood, K.L. A p38 Mitogen-Activated Protein   
    Kinase Inhibitor Arrests Alveolar Bone Loss in vivo. J Periodontology, 78(10):
    1992-1998, 2007.
9. Patil, C.S. and Kirkwood, K. L.  p38 Signaling in Oral-Related Diseases, Critical
    Reviews in Oral Biology & Medicine, J Dent Res 86(9):812-825, 2007.
10. Zhao W., M. Liu, K.L. Kirkwood. p38α Stabilizes Interleukin-6 mRNA via Multiple
     AU-Rich Elements. The Journal of Biological Chemistry, 283(4):1778-85, 2008.
11. Patil, C.S. M. Liu, W. Zhao, D. D. Coatney, F. Li, N. J. D’Silva, and K. L.
     Kirkwood. Targeting mRNA Stability Arrests Inflammatory Bone Loss, submitted,
     Molecular Therapy, 16(10), 1657-16664, 2008.
12. Rossa, C., Jr., K.L. Kirkwood. The Potential of p38 MAPK Inhibitors to Modulate
      Periodontal Infections, Current Drug Metabolism, 10(1): 55-67 2009.