Research in our laboratory is focused on methionine metabolism and its relationship to human disease. Mutations and polymorphisms in methionine metabolic genes have been implicated in a variety of human diseases ranging from rare genetic disorders to common diseases like cardiovascular disease and cancer. The current work in the laboratory focuses on two particular methionine metabolic genes, cystathionine beta-synthase (CBS) and methylthioadenosine phosphorylase (MTAP). Loss of the MTAP gene by homozygous deletion is observed in a variety of human tumors. We are studying the physiological effects of MTAP and its role as a tumor suppressor gene. We have recently found that MTAP deletion appears to play a role in cell invasion and metastasis. The second gene we are studying, CBS, encodes a protein that is responsible for the metabolism of homocysteine and mutations in CBS that cause clinical homocystinuria, the most common inherited disorder in methionine metabolism. Moderately elevated homocysteine levels found in the general population have been shown to be a risk factor in diseases of aging, such as coronary artery disease, stroke, peripheral vascular disease, neural tube defects, and age-related dementia. We are particularly interested in understanding the effects of missense mutations in CBS and in developing strategies to restore function to mutant proteins. We are also using mouse models to understand the mechanism by which severely elevated plasma homocysteine causes human disease.
Our laboratory is also interested in chemoprevention. We are examining the effectiveness of several compounds, including cyclooxygenase-2 (COX-2) inhibitors, proliferators activated receptor-g agonists (PPARg), and 4-methylthio-2-oxobutanoic acid (MTOB) in a mouse model for breast cancer.