Summer Research Opportunities Program 2009
Section on Lipid Sciences
Drs. Larry Rudel and Mark Brown
Dysregulation of cholesterol balance contributes significantly to coronary heart disease (CHD), the leading cause of death in the United States. Molecular mechanisms regulating the transport of cholesterol into and out of the body have been well-defined. It is generally accepted that cholesterol enters the body via intestinal absorption or endogenous synthesis, and is excreted out of the body via a hepatobiliary route, either as free sterol or following hepatic conversion to bile acids. Although it is believed that the hepatobiliary route is the major pathway for fecal cholesterol excretion in humans, we have recently found that fecal sterol loss is normal in mice unable to secrete cholesterol into bile. Our findings, along with others, suggest that the intestine may play an important role in the direct elimination of cholesterol, and this novel pathway will be the focus of summer research. The objective of this project is to understand the molecular mechanisms regulating non-biliary fecal sterol loss through the intestine, a poorly understood pathway that may play a quantitatively important role in whole body cholesterol balance and CHD. During the summer rotation, students will learn basics in mouse breeding, genotyping, and experimental design. They will also gain hands on experience in the laboratory practicing such techniques as Western blotting, lipid extraction, gene expression analysis, and enzymatic assays. In addition, the students will actively participate in several group discussions, lab meetings, and seminars to provide them with a base for the scientific process. The goal is to introduce students to integrative physiology, and to help them gain confidence in future endeavors in basic science research.
Drs. John Parks and Jeongmin Seo
Coronary heart disease remains the single largest cause of death in the US and is caused by accumulation of cholesterol in arteries. Cholesterol is transported in blood in lipoprotein particles, such as low density lipoproteins and high density lipoproteins (HDLs). Studies have shown that heart disease is inversely associated with HDL concentrations in blood, such that, individuals with high HDL levels are less likely to develop heart disease. HDLs have proteins, called apolipoproteins, on their surface that help determine the metabolism of HDL in blood. Recently, a new apolipoprotein (apoM) was discovered that associates with HDL, but its function is currently unknown. In our preliminary studies, we have found that apoM overexpression in cultured cells leads to the formation of larger HDL particles. This summer rotation will focus on experiments to determine the function of apoM expression on HDL metabolism using transgenic mice that overexpress apoM and anti-sense oligonucleotide treatment of mice to decrease apoM expression. Students will learn techniques of lipoprotein separation and quantification, including enzymatic assays and Western blot analysis, as well as mouse handling and husbandry. Students will also participate in lab meetings, seminars and other scientific meetings involving the Lipid Science faculty, students, and post-doctoral fellows.
Dr. Kazushi Inoue
The project in our laboratory is currently focused on the biological and biochemical characterization of the novel tumor suppressor Dmtf1 (cyclin D binding myb-like transcription factor 1). Dmtf1 is a critical regulator of the p19Arf-p53 tumor suppressor pathway. Dmtf1-knockout mice are prone to tumor development, especially lung carcinomas. We recently found that the human DMTF1 gene was deleted in 40-50% of human lung and breast cancers. We have recently identified a few Dmtf1-interacting partners by mass spectrometric analyses. The summer student will be engaged in molecular characterization of Dmtf1-interacting proteins and their roles in human cancer development.