LEON LEVY CENTER FOR ORAL HEALTH RESEARCH

LEON LEVY CENTER FOR ORAL HEALTH RESEARCH

University of Pennsylvania
School of Dental Medicine

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INTRODUCTION

The Center for Oral Health Research (COHR) was constituted in 1970 as the basic sciences research core of the Univrsity of Pennsylvania School of Dental Medicine. The University, which is a privately endowed nonsectarian institution founded by Benjamin Franklin in 1740, has played a significant role in the development of contemporary ideas in both the humanities and sciences. Currently, there are 12,000 undergraduate and 9,000 graduate and professional students.

The major mission of COHR is to cultivate biomedical and oral health relaed research activities. The Center recives considerable NIH support and is a major national site for oral and dental research. There is extensive collaboration with scientists in other schools of the University as well as with those of other institutions. COHR is located adjacnt to the School of Dental Medicine in the Leon of Veterinary Medicine, three blocks from the Medical School and within easy walking distance of the Hospital of the University of Pennsylvania and the Childrens Hospital of Philadelphia. For twenty years, COHR has trained undergraduate and graduate students as well as postdoctoral fellows and visitng scientists.

Scientists in COHR welcome inquiries from students and graduates in the life sciences concerning opportunities to participate in ongoing research.


All diseases may, by sure means be prevented or cured, not even excepting old age, and our lives lengthened at pleasures even beyond the antediluvian standard.
--Benjamin Franklin


INFECTION AND THE HOST RESPONSE

The ability of bacteria to colonize and viruses to infect cells represents a dynamic balance between virulence of the infectious agent and host responses. Scientists at COHR are utilizing a wide range of techniques in cell and molecular biology to characterize the interaction of host derived defense mechanisms with bacterial and viral virulence factors. Protein chemistry, gene cloning, immunology and electron microscopic techniques are being employed to dissect the molecular mechanisms involved in these processes.

Investigators are exploring the inflammatory response of neutrophils to bacteria. These studies have identified a number of host and bacterial derived factors which influence the ability of bacteria to cause disease. Oral bacteria can produce a potent toxin which specifically kills neutrophils and increases the infectivity of the microorganism. The gene for this leukotoxin has been identified, cloned and expressed in E. coli. Investigators are using a molecular biological approach to further dissect the molecule and understand its mechanism of action.

Another molecule isolated from oral flora is involved in immunoregulation. It suppresses the immune response by activating T-suppressor cells. Potentially, this factor could be used therapeutically as an immunosuppressive agent. This factor has now been identified as a member of the Cytolethal Distending Toxin family.

Faculty research is also directed at inflammation and diabetes as they relate to periodontal disease and the loss and repair of connective tissue and bone. In addition, work is currently directed on periodontal immune and inflammatory processes, mainly addressing the causes, development, and susceptibility markers of periodontal disease. Further, research at the SDM examines the relationship between periodontal/other oral diseases and systemic health and diseases such as diabetes and cardiovascular disease, involving research into inflammation, immunity, microbial pathogenesis, genetics, and systemic disease markers.

BONE, TEETH AND EXTRACELLULAR MATRIX

Cartilage and Bone Development: The skeletal system of vertebrates, consisting of cartilage and bone, undergoes a complex developmental pathway which is characterized by profound changes both in the composition of the extracellular matrix and in energy metabolism. During this developmental process, mesenchymal cells differentiate into chondrocytes, the cells that produce cartilage. In endochondral growth cartilage, a structure that mediates bone growth, chondrocytes mature and produce a mineralized matrix. Ultimately this matrix is replaced by mineralized bone. The cellular and molecular mechanisms mediating this developmental process are the subject of an extensive COHR research program.

COHR scientists are probing the molecular mechanisms regulating changes in collagen types during maturation of cells which form bone and cartilage, as well as those controlling the induction of a unique protein, type X collagen, during cartilage maturation.

Experiments are being performed to characterize the structure- function relationships of alkaline phosphatase, an enzyme which is expressed at high levels in all mineralizing tissues, yet whose role in the calcification process is enigmatic. Related studies are aimed at elucidating the metabolic status of the cells of the growth plate and relating changes in gene expression to oxidative metabolism, cell maturation and calcification.

Another area of investigation involves the role of mesechymal stem cells in the site specific differential response of bone to radiation and bisphosphinate treatment.

Enamel: Tooth enamel is the hardest tissue in the human body. Its unique class of matrix proteins, amelogenins, participate in mineral formation. Center investigators are exploring the structure and function of these proteins by cloning the DNA coding sequences into plasmids for expression in E. coli. Transgenic mice are being used to study the effects of gene alteration in vivo and to create an animal model for the human enamel defect hereditary amelogenesis imperfecta.

VIRAL INFECTION Herpes simplex viruses (HSVs) cause a variety of human disease, including cold sores, eye and genital infections, and encephalitis. HSV glycoproteins are incorporated into the virion envelope and are expressed on infected cell membranes. Three glycoproteins, gB, gD, and gH, are eseential for viral infection and have been implicated in the entry process. A major objective is to define the steps of virus entry. The focus of the studies is to detrmine the importance of each of these glycoproteins for virus survival or pathogenesis in human.

Four glycoproteins, gC, gE, gG and gI, may play a significant role in pathogenesis. The glycoproteins gE and gI function as Fc receptors for human IgG; gC is a receptor for complement components C3b and iC3b and may modulate complement mediated host responses. At present, ongoing studies concentrate on gC and gD.

Recent studies have shown that gD interacts with a specific cell receptor; current and future experiments are being directed at this receptor interaction and its importance in the entry process. In addition, gD is being tested as a potential human subunite vaccine. To map the portion of gD which is critical for its function, researchers COHR have used site-directed mutagenesis techniques to create mutations in the gD gene. Other studies are focused on the effects of those mutations, using immunological, as well as functional assays. These studies may also provide information about the folding of gD into its native structure.

Experiments are in progress to identify the interaction of gC with the complement of component C3b. Thus far, several regions of gC-1 and gC-2 have been implicated in C3b receptor activity and one of these regions shows homology with a portion of the human complement receptor CRI. The goal is to evaluate the role of the glycoproteins in HSV infection adn pathogenesis in order to design a paradigm for intervention.

CENTRAL FACILITIES

Major advantages of the research center of the School of Dental Medicine are common facilities which provide specialized technology and expertise as well as clinical populations for COHR investigators.

Ultrastructural and Imaging Analysis Core Facility: The facility prepares bological tissues for most types of ultrastructural studies. The facility contains a JEOL 100 CXII transmission electron microscope and a JEOL 330 A scanning electron microscope equipped with a KEVEX energy dispersive X-ray microanalysis unit. Routine analysis is provided as a service while more extensive work usually involves collaborative arrangements with the Directors, Dr. Edward Macarak & Dr Ellis Golub.

Flow Cytometry and Cell Sorter Laboratory: This facility, directed by Dr. Bruce Shenker, has been developed for the purpose of analyzing and sorting cells and chromosomes. It is equipped with a Becton Dickinson FACStar Plus flow cytometer and dual lasers. This technology includes six parameter analyses (four color fluorescence), light scattering, calcium imaging and cell cycling. The facility utilizes state-of-the-art computer analysis and presentation graphics.

FOR MORE INFORMATION ABOUT COHR COMMUNICATE WITH:

Dr. Bruce Shenker, Associate Dean for Research, School of Dental Medicine, Leon Levy Center for Oral Health Research, University of Pennsylvania, 4001 Spruce Street, Philadelphia, PA 19104-6003.

Telephone: 215-898-5959 FAX: 215-573-2050


INVESTIGATORS

  • Marjorie Jeffcoat
  • Kelly Jordan-Sciutto
  • Denis Kinane
  • Jonathan M. Korostoff
  • Claude Krummrnacher
  • Edward Lally
  • Edwin Macarak
  • Francis Mante
  • Claire Mitchell
  • Robert Ricciardi
  • Bruce Shenker
  • Yan Yuan


  • This page accessed 107265 times since December 22, 2010
    This file last updated on Wednesday December 22, 2010
    For more information contact Dr. Ellis E. Golub (ellis@biochem.dental.upenn.edu)