Our group discovered an endothelial cell
protein, GPIHBP1, that is required for the processing of
triglyceride-rich lipoproteins. Genetic defects in GPIHPB1 cause
severe hypertriglyceridemia. Over the next few years, we plan
to pursue the cell biology, structure, and clinical relevance of
We have also
investigated the importance of lipid modifications of proteins.
Much of this work is focused on the nuclear lamins, which are
building blocks for the nuclear lamin A--a structural
scaffolding for the cell nucleus. A defect in one of the nuclear lamins, prelamin A, leads to progeria, a “precocious aging”
syndrome in children. The prelamin A in children with progeria
cannot be processed normally, resulting in the accumulation of a
“lipidated” prelamin A. We hypothesized that drugs designed to
block the lipid modification would ameliorate the disease
phenotypes of progeria. To test this hypothesis, we generated
two gene-targeted mouse models of progeria. A drug designed to
block the lipidation of prelamin A reduced the severity of the
disease phenotypes in both models. Drug trials in humans are
Over the next few
years, we plan to define the in vivo
importance of two other nuclear lamins, lamin B1 and lamin B2.
focuses on molecules relevant to human disease. We make use of a
wide variety of techniques in molecular and cellular biology,
including the creation of genetically modified mouse models.