U’s Young Scientist Unraveling Mystery Behind Heart Disease

Although 16 million Americans have diabetes and 75 percent of them die from heart disease or stroke, little is known about how diabetes affects the heart.

Researchers at the U hope to change that soon. The School of Medicine received a $2.5 million grant from the National Institute of Health last October to take a lead role in solving that puzzle.

Dr. Donald McClain, principal investigator of the project, hopes to develop a complete model of the disease’s mechanisms in mice, from how diabetes affects heart development to how it impedes healing after a heart attack. This “gold standard” could lead to better diagnosis and treatment of cardiovascular diseases in diabetics.

Such a global understanding of the disease requires expertise in several fields. McClain assembled a team of geneticists, molecular biologists and physiologists to perform experiments at all levels “from the whole mouse to the genes and cells.” This multi-disciplinary approach is now possible because all the technologies have finally arrived.

“Genetic techniques got ahead of our ability to examine the mouse physiologically,” McClain said. “We [now] have quite a setup to look at [this animal].”

To study the problem, co principal investigator Dr. Dale Abel created special strains of mice through DNA manipulation. Using a novel technique called “conditional gene targeting,” Abel induced genetic defects in some of these mice so their heart muscle cells cannot fully utilize glucose (an important source of energy in most cells). Other strains of Abel’s mice cannot regulate glucose level in their blood and cells. These mice lack the gene to make insulin receptors, which respond to the hormone insulin to regulate glucose absorption into the cell.

Although the mouse models are tailor-made for the study, they still pose several challenges to the researchers, said Abel, an assistant professor at the division of endocrinology, metabolism and diabetes.

“Their hearts are the size of a fingernail, and we can take only very small blood samples.” Abel said. The miniature model required the team to develop new technology, such as an implantable device that can measure blood pressure in the mouse continuously for 12 weeks.

“Although we’d modeled the animal as closely as possible, men and mice are not the same thing,” Abel continued. “For example, it’s very hard to reproduce arteriosclerosis [hardening of the arteries] in mice…We will have to extrapolate what we find into humans to see if our hypotheses hold true.”

Abel and McClain’s work complement each other in studying how the heart uses glucose. While Abel will be working on how glucose is delivered to the cells, McClain will study how the cells react to it.

Recruited by McClain, Abel was working on diabetes at Harvard when the two met at medical conferences. Eager to advance diabetes research at the U, McClain has been recruiting young promising scientists like Abel to the U. After a few visits, the 39 year-old Abel thought the U would be a “good opportunity to increase my own research output.” He joined the U faculty in 2000 and has won two national awards recently distinguishing him as an outstanding young scientist.

The two are flanked by experts of their fields. Dr. Sheldon Litwin has studied the role of calcium in heart muscle cells and performs echocardiograms (ultrasound images) on mice routinely. The Eccles Institute of Human Genetics’ Drs. Jean-Marc LaLouel and Robert Weiss are experts in mouse genetics. And Dr. Guy Zimmerman studies how inflammation affects blood vessels.

The project makes the U part of a consortium studying the effects of diabetes on a number of organs. While the U concentrates on heart diseases, laboratories at other campuses will study how diabetic complications affect the kidney, blood vessels and the nervous system. The consortium includes the Albert Einstein College of Medicine, University of California at Los Angeles, University of Michigan, University of North Carolina and Rockefeller University.

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