Philip Trackman

About

Research in Dr. Trackman’s laboratory is focused on the regulation of extracellular matrix accumulation in mineralized and non-mineralized normal tissues, and in pathologies in which extracellular matrix accumulation is affected. Studies, which utilize cell culture, animal models, and human tissues, encompass a wide range of experimental approaches derived from the disciplines of biochemistry, enzymology, cell biology, and quantitative biology. Goals of these studies are to obtain a greater understanding of the molecular and cellular basis for gingival overgrowth and other fibrotic diseases, and to understand mechanisms of osteopenia that occurs as a complication of type I diabetes. Recent important findings show that oral fibroblasts are resistant to the effects of certain inflammatory factors, and that this resistance contributes to the elevated expression of connective tissue growth factor (CCN2/CTGF). This growth factor, in turn, contributes to gingival overgrowth and oral fibrosis. In addition, the biological process of epithelial to mesenchymal transition has been identified as a contributor to gingival overgrowth. These understandings provide new avenues for therapeutic approaches to prevent and treat gingival overgrowth. The mechanism by which lysyl oxidase acts as a tumor suppressor is under investigation. Dr. Trackman’s laboratory has made the novel discovery that the tumor suppressor function of lysyl oxidase resides in the propeptide (LOX-PP) region of a proenzyme precursor. This propeptide is released from the proenzyme by extracellular proteolytic processing, and the released propeptide inhibits growth of tumor cells and tumor formation. A focus of the laboratory is to identify mechanisms by which the lysyl oxidase propeptide can suppress tumor formation or tumor growth and tumor metastasis. A major target of LOX-PP was found to be the fibroblast growth factor receptor-1 (FGFR1). Intracellular targets are now under investigation. A polymorphism in LOX-PP was found to have impaired ability to suppress tumors in mice, and is a risk factor for breast cancer in estrogen receptor-negative breast tumors in humans. rLOX-PP is effective as an inhibitor of tumor growth in xenograft models. The potential use of LOX-PP as a cancer pharmacologic agent is being evaluated in continuing preclinical and mechanistic studies. Additional studies are evaluating the mechanisms and inhibitors of lysyl oxidase and lysyl oxidase like-2 as anti-fibrotic and anti-cancer agents. Finally, regulation of lysyl oxidase isoforms in diabetic ostepenia is being pursued in light of the fact that lysyl oxidase-dependent cross-linking of collagen in bone is abnormally low in diabetes, and contributes to reduced bone strength.

Education