Award Focuses on a Protein's Structure and Interactions
Atherosclerosis — hardening of the arteries — generally is not considered a pediatric condition, but the formation of fatty streaks that contribute to the condition starts in utero and builds up over decades.
Although children usually have low cholesterol concentrations, by the age of 12 to 14 years approximately 70 percent of children have fatty streak lesions that may eventually contribute to atherosclerosis. Obtaining information at the molecular level about this process may lead to the understanding of early pathophysiological events in atherosclerosis.
Serum lipoproteins — complexes of fats and proteins present in the blood — play a role in lipid and cholesterol transport and in the development of atherosclerosis. One of the structural proteins of lipoproteins, called apolipoprotein (apo) E, is involved in the metabolism of cholesterol and triglycerides. ApoE prevents plaque buildup by interacting with lipids and molecules on a cell's surface like low-density lipoprotein receptors (LDLR) and glycosaminoglycans. However, the structural basis for these interactions is not fully understood.
ApoE is also part of lipoproteins in the central nervous system where it mediates neuronal repair, remodeling and protection against dementia and Alzheimer's disease. There are three major forms of apoE, some of which can increase the risk of developing atherosclerosis and Alzheimer's disease.
With support from the National Institutes of Health, Sissel Lund-Katz, Ph.D., of the Lipid Research Group in the Division of Gastroenterology, Hepatology and Nutrition at The Children's Hospital of Philadelphia, is leading a study on the molecular features that control apoE's binding to lipids, lipoprotein particles and cell surface receptors.
As part of the $1.6 million, four-year award, Dr. Lund-Katz and her colleagues will also investigate how the receptor binding domain for apoE controls its binding to glycosaminoglycans as compared to members of the LDLR family. The team will also characterize how apoE interacts with cells to create high-density lipoprotein particles, which protect against harmful deposition of cholesterol in tissues.
Understanding the molecular basis for apoE's different activities may lead to the design of treatments or preventative strategies for atherosclerosis and other conditions.