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 Thomas E. Landerholm
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My laboratory studies the cell and molecular biology of the cardiovascular system as it develops in the embryo, with a particular emphasis on the coronary arteries that feed the heart. Blockage of the coronary arteries due to atherosclerosis, or coronary artery disease, is the single greatest killer of Americans today. This blockage is largely the result of vascular smooth muscle cells (vSMC) from the walls of the artery leaving their contractile adult state, migrating into the inner endothelial layer of the artery and secreting extracellular matrix materials, as though they were forming a scar. Migration and high levels of matrix secretion are normal activities for vSMC early in arterial development in the embryo but are not common in the adult artery. The vSMC found in the diseased artery also express many genes that are normally expressed only by embryonic vSMC. These apparent reversals of normal development make an understanding of coronary vSMC differentiation imperative to our understanding of the disease process.

Cell differentiation is the process in embryonic development whereby cells with multiple potential fates assume their final form. The coronary arteries are found on the surface of the adult heart beneath a tough, fibrous layer called the epicardium. Recent research has shown that the vSMC of the coronary arteries first reach the heart surface as undifferentiated cells that retain the ability to become epicardial cells, coronary vSMC, or matrix-secreting fibroblasts. The source of these cells is the proepicardium (PE). The decision of a small percentage of PE cells to become vSMC appears to coincide with their close physical association with endothelial cells, myocardial cells and the extracellular matrix at the future sites of artery formation. Current studies in my laboratory focus on the external signals that stimulate changes in vSMC progenitor cells and the resultant molecular changes that occur inside those cells to produce adult vSMC. We currently focus on three growth factors found in the region of coronary artery formation in the embryo, transforming growth factor beta (TGFbeta), platelet derived growth factor (PDGF) and sonic hedgehog (shh). These protein groeth factors have been implicated in the differentiation of SMC elsewhere in the embryo. Thus, these studies are based on the questions: Can TGFbeta, PDGF and/or shh determine the cell fate decisions of the undifferentiated progenitors of coronary vSMC? By what intracellular mechanisms are these changes produced?

My laboratory is an integral part of two rapidly growing research groups in the College of Natural Sciences and Mathematics and the Department of Biological Sciences at CSU, Sacramento. The Biomedical Research Group is a group of four investigators, Drs. Christine Kirvan, Hao Nguyen, Thomas Peavy and myself, doing research into the Cell and Molecular Biology of human pathophysiologies. Our research interests vary widely, including neurological autoimmune disorders, cancer, fertilization and coronary artery disease, respectively, but we share many of the same research methods and technical expertise. These techniques include eukaryotic cell culture, microdissection, immunohistochemistry, protein and nucleic acid quantification, and many others. The Biomedical Research Group Laboratories are found in the basement of Sequoia Hall in Laboratory Suites 16 and 18.

I am also a member of the Molecular Biology Interdisciplinary Group (MBIG) comprised of faculty from the Departments of Biological Sciences and Chemistry. MBIG faculty and students use the tools of molecular biology for a broad range of applications, including the biochemistry of HIV and lipid disorders, DNA forensics, bacterial pathogenesis, plant physiology, the biology of heart disease and cancer, and the genetics of bat and bird populations in California. The MBIG facility is a core suite of nine dedicated rooms that house cell and molecular biology instrumentation including large equipment, murine animal facilities, a computer and poster printer, eukaryotic cell culture, clean pre-PCR preparation, prokaryotic cell culture and plasmid preparation. These facilities encompass a total area in excess of 2500 square feet and including major equipment such as two DNA sequencers, a chemi-luminescent detection and gel-documentation system, a Sorvall centrifuge, a Beckman ultracentrifuge, 37oC shaking and culture incubators, two level II biosafety hoods, a water-jacketed CO2 incubator, an inverted microscope, -80oC and -20oC freezers, refrigerators, thermocyclers, and power supplies and accessories for nucleic acid analysis. The MBIG Laboratories are found in the basement of Sequoia Hall in Laboratory Suite 28.

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