Research in the Forsyth Department of Cytokine Biology focuses on the role of polypeptide mediators, including cytokines, chemokines, neuropeptides and other extracellular signaling molecules, in regulating diverse biological phenomena including inflammation and resistance to infections. Areas of investigation focus on host responses to oral and systemic microbial infections, vaccine development, immunoregulation of bone metabolism, osteoclast and osteoblast differentiation and regulation, neuroskeletal interactions and developmental biology of the craniofacial complex.
A major thrust of this research has concentrated on osteoimmunology, the study of the immune and inflammatory mechanisms that lead to infection-stimulated bone destruction in the oral cavity. These studies have demonstrated the role of Th1 and Th2 T cells and proinflammatory cytokines in regulating osteoclast differentiation and activation in response to periodontal and endodontic infections. Complementary studies have identified host responses that protect against oral infections and prevent such infections from destroying tissue or disseminating systemically. Research topics include the critical roles of anti-inflammatory cytokines (IL-10, IL-6 and TGF), T helper cells (Th0, Th1, Th2, Th17) and T regulatory cells in preventing or exacerbating bone loss. In addition, the Department investigates the roles of antimicrobial antibodies and the mechanisms of neutrophil chemotaxis and priming in protecting against disseminated infection.
By using a variety of antigen-discovery strategies, including T-cell expression cloning and decoding of microbial antigens produced in vivo during infection, Department members have identified candidate antigens to protect against or diagnose diseases caused by oral pathogens, such as Porphyromonas gingivalis, and systemic pathogens like Mycobacterium tuberculosis. Vaccine candidate antigens are used in immunization regimens that bias the T-cell response toward the protective phenotype ( Th2/Treg or Th1/Th17 respectively). Diagnostic candidate antigens are used to develop either traditional serological tests or capture ELISA and rapid tests that can detect microbial antigens produced in vivo during disease. Several unique M. tuberculosis antigens found in the urine of patients with pulmonary tuberculosis have been extensively tested in pre-clinical studies to define their possible utility as either vaccine candidates or diagnostic markers of active disease.
During the past decade, the Department has carried out detailed phenotypic analyses of osteoclasts, using differential hybridization and gene arrays. These studies have identified many molecules critical to the function of this cell type, including cathepsin K, the proton-pump subunit ATP6i, the signaling molecules RGS10B and RGS12, the cation-proton antiporter NHA-oc, the serotonin transporter (5-HTT) and many 5-HT receptors. Gene-knockout studies have established the function of many of these molecules.
Findings that osteoclast function is regulated by the serotonin system, as well as by neuropeptides, have contributed substantially to the emerging field of neuroskeletal biology. The Department has also confirmed unequivocally that Th1 response is involved in aggravating periapical bone destruction caused by P. gingivalis. Moreover, the Department is exploring the role of cytokines and other signaling molecules, including transcription factors, in the development of dental and craniofacial tissues and organs. These efforts have principally centered on the role of molecules that affect osteoblasts, osteoclasts and enamel-forming ameloblasts.
Antonio Campos-Neto, M.D., Ph.D. (Department Head)
Richard Niederman, D.M.D.
Philip Stashenko, D.M.D., Ph.D.
John Bartlett, Ph.D.
Yi-Ping Li, Ph.D.
Ricardo Battaglino, Ph.D.
Hajime Sasaki, D.M.D., Ph.D.
Shuying Yang, M.D., PhD.
Emad AlShwaimi, D.D.S.
Ning Li, Ph.D.
Rachel Lorenz, Ph.D.
Shi-Liang Ma, Ph.D.
Leslie Morse, M.D.
Ramaswamy Sharma, Ph.D.
Coralee Tye, Ph.D.
Kader Yagiz, Ph.D.
