Molecular Basis of Cardiovascular Diseases

The focus of my laboratory is to identify the signaling pathways that control the pathophysiology of cardiovascular diseases.  Three projects are currently under investigation in my lab.

Signaling pathways controlling cardiac hypertrophy: Cardiac hypertrophy is an early adaptive process that allows the heart to maintain or increase cardiac output in response to increased workload. We are interested in using both cellular systems and transgenic mice as our experimental methods to investigate the essential role of multiple signaling pathways in cardiac hypertrophy. Our current studies involve the analysis glucose and mitogen activating protein kinase (MAPK) cascades in calcineurin signaling and mTOR signaling in cardiac hypertrophy.

mTOR, a placental growth signaling sensor:  A major cell type controlling the development of the placenta is the trophoblast.  The intracellular signaling pathways acting downstream of mitogenic factors and nutrients to regulate trophoblast proliferation and placental development are poorly understood. We showed that metabolites of the GFAT (glutamine fructose amidotransferase) reaction act upstream of mTOR and function as a nutrient sensor to regulate trophoblast cell proliferation in response to glucose.  Overall our studies show that growth factor and nutrient signaling converge at tuberin, an upstream regulator of mTOR and that mTOR functions as an important placental growth signaling sensor.  Therefore, our current research is to focus on determining the regulatory role of GFAT metabolites on mTOR signaling as nutrient sensors for normal and abnormal trophoblast trophoblast cell proliferation (such as diabetic gestation, and intrauterine fetal growth retardation) and potential role of glycosylation by UDP-N-Acetyl glucosamine in these pathways (see figure).

Angiotensin receptor autoantibodies and the pathophysiology role in preeclampsia: Preeclampsia (PE) affects approximately 8% of all pregnancies, has been extensively studied, yet remains poorly understood.  Recent studies from our laboratory indicate that the persistent presence of angiotensin AT1 receptor agonistic autoantibodies (herein termed AT1-AA) are a risk factor for the onset and development of PE. Therefore, our long-range goal is to evaluate the contributions of AT1-AA to PE and explore the immunological origins of these autoantibodies.

Xia, Y., Wen, H., Bobst, S., Day, M-C, and Kellems, R.E., “Maternal autoantiibodies from preeclamptic patients activate angiotensin receptors in human trophoblast cells" J. Soc. Gynecol. Investig, 10: 82-93(2003).

Xia, Y., Wen, H., Young, M., Guthrie, P., Taegtmeyer, H., and Kellems, R.E., “mTOR and PKA signaling mediate the cardiac transcriptional response to glutamine" Journal of Biological Chemistry 278(15):13143-50 (2003).

Thway, T.M., Shlykov, S.G., Day, M-C, Sanborn, B.M., Gilstrap, L.C., Xia, Y. and Kellems, R.E. "Antibodies from preeclamptic patients stimulate increased intracellular Ca 2+ mobilization through angiotensin receptor activation", Circulation, 110 (12):1612-9 (2004). 

Bobst, S., Day, M-C., Gilstrap, L.C.,  Xia, Y. and Kellems, R.E.,  “Maternal Autoantibodies from preeclampsia patients activate angiotensin receptor on human mesangial cells and induced interleukin-6 and plasminogen activator inhibitor-1 secretion” The American Journal of Hypertension, In Press (2005)

Wen, H.Y., Abbasi, S., Kellems, R.E and Xia, Y,." mTOR: A Placental Growth Signaling Sensor” Trophoblast Research, In Press (2005)