Biochemist wins grant to develop cellular molecular probes capable of measuring cholesterol levels

Alejandro P. Heuck, a biochemist at the University of Massachusetts Amherst, has received a four-year, $308,000 grant from the American Heart Association to develop molecular probes capable of measuring cholesterol levels in the membranes of individual cells.

Based on proteins produced by bacteria, the probes will be useful to evaluate the effect of new drugs designed to reduce cholesterol levels and could potentially be used as a diagnostic tool in humans with atherosclerosis (hardening of the arteries) and Alzheimer's disease.

“Mammals have developed sophisticated and complex mechanisms to maintain cellular cholesterol levels in a narrow range. These control mechanisms are overwhelmed in the late stages of diseases like atherosclerosis, often with severe consequences,” says Heuck. “Development of these molecular probes will allow us and others to precisely assess cholesterol levels in cell membranes and to study its regulation when cells are subjected to different stimuli or drug treatments.”

Heuck will use a protein from the pathogenic bacteria Clostridium perfringens that has evolved to recognize cholesterol and bind to it when high levels are present in a cell membrane. The binding region of the protein will be modified to alter the level of cholesterol it will bind to. “In particular, we are looking for mutant proteins that recognize only low or high levels,” says Heuck.

Heuck will generate numerous probes that bind selectively to cells containing a specific level of cholesterol and label each probe with a different fluorescent dye. These fluorescent-labeled molecules will be used to estimate the cholesterol content of cells subjected to cholesterol loading or depletion. Initially, the probes will be used to study cholesterol regulation in the cell membranes of macrophages, since these immune system cells are involved in the formation of the arterial deposits that characterize atherosclerosis.

The grant, which began Jan.1, is an American Heart Association Scientist Development Grant to support highly promising beginning scientists. The program
is designed to encourage and adequately fund research projects that bridge the gap between completion of research training and readiness for successful competition as an independent investigator.