Investigators and Program Directors

Derek Symula

Research Scientist, Wadsworth Center, Mammalian Genomics
Assistant Professor, School of Public Health, Biomedical Sciences

Ph.D., University of Wisconsin-Madison (1995)
Postdoctoral training, Lawrence Berkeley National Laboratory

Research Interests

An elegant, complex system has evolved to manage cellular cholesterol levels. Cholesterol is an essential nutrient but too much is toxic to the cell. As a result, defects in cholesterol homeostasis contribute to many human diseases. Heart disease is perhaps the best-known cholesterol-related disease, but cholesterol also impacts steroid hormone synthesis, pre-natal development, and cancer, among others.

Gene discovery using expression profiling
My laboratory is using expression profiling and classification algorithms to identify new genes involved in cholesterol metabolism. We are profiling a large number of mouse embryonic stem cell lines, each mutant in a gene relevant to cholesterol metabolism (the "cholesterol" class) or in a well-studied gene with no known relationship to cholesterol (the "non-cholesterol" class). The data from these cell lines will be analyzed using supervised learning methods such as support vector machines (SVM) to identify the genes that robustly distinguish the cholesterol class from the non-cholesterol class. These classifiers will then be used to screen a much larger set of mutant cell lines to identify new mutants in the cholesterol class that can be studied in vivo.

Neurodegeneration in Niemann-Pick Type C disease
One of the fundamental, but poorly understood, aspects of cholesterol metabolism is how cholesterol is trafficked around a mammalian cell. Lipids such as cholesterol are not water-soluble and must be transported by a membrane or protein. While several cholesterol-trafficking proteins have been identified, the functions of each have not been elucidated. Loss of either of two genes, Npc1 or Npc2, leads to lysosomal accumulation of cholesterol and symptoms including neurodegeneration and liver, spleen, and lung pathology. We are using genetic approaches in mice deficient in the Npc2 gene to identify "modifier" genes that attenuate the mutant phenotype. These genes will help us understand why a cholesterol trafficking defect leads to a neurodegenerative disease and may yield insight into the relationship between cholesterol and Alzheimer's disease.

Contact Information

E-mail: symula@wadsworth.org.