Our team also consists of research faculty located at the VA in White River Junction, VT. Read more about VA faculty research below:
Constance E. Brinckerhoff, PhD
Professor of Medicine and Biochemistry
Dr. Brinckerhoff's laboratory studies Matrix Metalloproteinases (MMPs), enzymes with the traditional role of degrading the extracellular matrix, but also with new and novel functions that include activating receptors and growth factors, mediating apoptosis and facilitating angiogenesis. The focus is on the collagenases (MMP-1 and MMP-13) that mediate connective tissue destruction in arthritic diseases and that contribute to tumor invasion and metastasis. She and her colleagues are investigating the genetic and epigenetic mechanisms that regulate the over expression of these enzymes, with the goal of specifically blocking their aberrant expression and reducing disease pathology.
Seth Anderson Brooks, PhD
Associate Professor of Research, Department of Medicine
In October 2005, Seth successfully renewed his Merit Review Grant with a project titled "Identification of Proteins Mediating Posttranscriptional TNF-a Expression." This project expands on his previous work examining TTP control of TNF-a mRNA stability to identify novel proteins that regulate TNF-a posttranscriptional expression. This project has moved quickly, with one manuscript title in submission: TTP Regulates TNF-a mRNA Stability via a Proteasome Dependent Mechanism and Inhibition of TTP Function Requires the Combined Action of the ERK and p38 Pathways.
In addition to his own research, Seth is an active collaborator with other Dartmouth and VA researchers. He and his mentor continue to discuss research directions and specific of cytokine posttranscriptional regulation, as well as share reagents. Seth collaborates with his VA colleagues, Matthew Vincenti and Roy Fava, assisting both with research design and with troubleshooting ideas, as well as performing specific experiments related to his area of expertise. Seth also has ongoing translational research collaboration with Drs. Michael Fanger, Mark Ernstoff, and Camilo Fadul. This work titled "A phase II Feasibility Study of Adjuvant Intra-Nodal Autologous Dendritic Cell Vaccination for Newly Diagnosed Glioblastoma Multiforme (DMS-0536)" examines the feasibility of autologous dendritic cell vaccination combined with chemotherapy as a treatment for glioblastoma multiforme.
Seth is an active member of the American Association for the Advancement of Science and the American Association of Immunologists. He currently serves on the Molecular Biology and genetics study section for the Arthritis Foundation. At the VA, he serves on the Research and Development Committee, which is charged with reviewing all research proposals at the VA, and the Space Allocation Committee.
Roy A. Fava, PhD
Research Associate Professor
Dr. Fava began his research in Rheumatology as the direct result of his early involvement in the discovery of TGF/beta. His laboratory was the first to report the presence of TGF/beta in synovial fluids in Rheumatoid Arthritis (RA). They were also the first to demonstrate the potential involvement of TBF/beta in arthritic inflammation, angiogenesis, and vascular permeability by injection into the articular joint space in rodent model. They next investigated angiogenesis in RA and demonstrated for the first time the presence of VEGF and its receptors in human synovial tissues and fluids.
Dr. Fava and his colleagues shifted interests to immune mechanisms in 1997, and implicated the involvement of the lymphotoxin-beta receptor axis in arthritis by use of a systemic antagonist of this pathway. This demonstration is the foundation for clinical trials currently underway with this antagonist. Currently, they are investigating the efficacy of this antagonist in a murine model for Sjögren's Syndrome, based on the known importance of the pathway to ectopic lymphoid tissue development.
Thomas H. Taylor, MD
Associate Professor of Medicine
In his capacity at the VA Medical Center in White River Junction, Dr. Taylor has continually served as Section Chief for both Rheumatology and Infectious Disease since 1978.
Dr. Taylor has served on numerous Medical School and VA committees. He currently serves as a member of the Infection Control Committee, Physicians Advisory Group on Bioterrorism, Intern Selection Committee, as well as a Pharmacy Antibiotic Subcommittee. He was elected to the Board of the Dartmouth affiliated ACTS Group, a volunteer organization that sponsors a clinic in El Rosario, Honduras. Dartmouth Medical students accompany him in order to gain valuable work experience in a clinic with meager resources. Dr. Taylor utilizes vacation time to see patients and supervise medical students in this small village located in an agriculturally deprived region. He has participated in six national and international studies, in some cases as an executive committee member. All of these studies were done by the VA cooperative group, and reflect the VA at White River Junction as one of the major contributing sites.
Dr. Taylor's research activities include publications on Methotrexate in rheumatoid arthritis, use of Sulfasalazine in psoriatic arthritis, Ankylosing Spondylitis, and Reiter's disease, the use of Doxycycline to eradicate Mycoplasma infection in patients with Gulf War Syndrome, and treatment of gout. He has published a number of different book chapters reflecting reviews of infectious arthritis and other rheumatologic concerns. He has also published journal articles that reflect a broad spectrum of rheumatologic concerns including Methotrexate and Oral Gold treatments of Rheumatoid Arthritis. He has also participated in several articles on physical examination in rheumatic diseases, an area that he is an acknowledged expert in.
Tom has been the recipient of a number of Cooperative VA grants as a co investigator and continues in that capacity presently in a very important trial in the comparison of "triple therapy" versus TNF Inhibitors, which is just now beginning to enroll patients.
Matthew P. Vincenti, PhD
Research Associate Professor
The Matrix Metalloproteinases (MMP) are a family of zinc and calcium-dependent endopeptidases that control the deposition of a wide range of matrix proteins during normal development and wound healing. MMP expression is elevated in diseases such rheumatoid arthritis, osteoarthritis and osteoporosis, leading to significant and permanent connective tissue destruction. MMP-1, MMP-13 and MMP-9 are secreted by synovial fibroblasts, chondrocytes, and osteoclasts, respectively. The inflammatory cytokines IL-1 and TNF promote expression of these enzymes by these cells, and this is thought to contribute directly to pathologic degradation of cartilage and bone.
Research in Dr. Vincenti's laboratory examines IL-1-dependent stimulation of MMP-1 in synovial fibroblasts and chondrocytes. These studies have established that IL-1 activation of the nuclear factor-kappa B (NF-κB) and the extracellular signal regulated kinase (ERK) pathways are critical processes for transcriptional activation of MMP-1 in these cells. Ongoing research is defining specific components of these pathways that are involved. Specifically, they have found that RelA and Bcl-3 are two NF-κB family members that are absolutely required for gene activation. Furthermore, IL-1 activation of the ERK pathway leads to phosphorylation of the transcription factor C/EBPβ, which directly binds to the MMP-1 promoter and facilitates transcription.
A second project in the laboratory investigates a group of plant-derived compounds known as triterpenoids. These compounds inhibit inflammation and reduce inflammation-induced MMP gene expression. TP-222, which is a triterpenoid that is highly bioavailable through oral administration to mice, effectively inhibits MMP-13 gene expression by chondrocytes and MMP-9 expression by osteoclasts. They are particularly interested in the molecular mechanisms through which TP-222 reduces MMP mRNA levels in these cells. It is hoped that this work will lead to the development of novel drugs that block cartilage destruction in arthritis and bone erosion in arthritis and osteoporosis.