September 12, 2008

Aliquots — Research highlights from VUMC laboratories

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We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to:

Cell therapy to clear clogged arteries

Once atherosclerotic plaques take hold, reversing this accumulation of cholesterol and immune cells on artery walls is difficult. Yan Ru Su, M.D., MacRae Linton M.D., Sergio Fazio M.D., Ph.D., and colleagues are investigating cell-based therapies to reverse atherosclerosis. Previously, the researchers inserted apoAI, a protein that helps clear cholesterol from arteries, into mature mouse bone marrow cells. The cell therapy reduced atherosclerotic lesions when injected into atherosclerosis-prone mice. But apoAI expression was suboptimal, limiting its therapeutic usefulness.

The researchers have now introduced apoAI into hematopoetic progenitor cells – self-renewing cells that give rise to all mature bone marrow and blood cells – using a more efficient lentiviral vector and a promoter that enhances expression of apoAI in macrophages, key cellular components of atherosclerotic plaques. They found that transplantation of these apoAI-expressing stem cells reduced the size of atherosclerotic lesions by 50 percent in atherosclerosis-prone mice compared to control mice, without altering plasma lipid levels. These results, reported in the August Arteriosclero-sis, Thrombosis and Vascular Biology, set the stage for developing cell-based therapies to reverse atherosclerosis.

— Melissa Marino

How to build a DNA biobank

Advances in understanding how genetic variants cause disease and modulate responses to drugs promise to usher in an era of personalized medicine. But identifying the links between genes and disease – or other characteristics – remains a challenge and will require large datasets of DNA and clinical information.

Dan Roden, M.D., and colleagues have been developing a large DNA biobank – a repository of de-identified (no identifying patient information) genetic samples matched with clinical data from electronic medical records. They report in the September Clinical Pharmacology & Therapeutics the implementation of this resource, including ethics review and community input, “opt-out” procedure development, and the sample and record de-identification process. The Vanderbilt DNA biobank is growing at the rate of 700-900 samples per week; by the end of 2010, it should include more than 130,000 samples.

The researchers acknowledge that technological and biostatistical challenges remain in utilizing the resource – which should be accessible by Vanderbilt investigators within a year – and expect that it will provide a test bed for implementing potential solutions.

— Leigh MacMillan

Bacteria ‘hijack’ stomach cells

The corkscrew-shaped bacterium Helicobacter pylori infects nearly half the world’s population and is the strongest known risk factor for stomach ulcers and gastric cancer. Yet only a fraction of those infected with H. pylori develop malignancy.

H. pylori strains that carry the cag pathogenicity island – a set of proteins that allows the bacterium to inject its components into stomach cells – increase disease risk. Richard Peek Jr., M.D., and colleagues are investigating how H. pylori cag+ strains influence disease progression in mice. In the Aug. 29 Journal of Biological Chemistry, they report that the cag system switches on a stomach cell receptor for the bacterium, called decay-accelerating factor (DAF), offering the first evidence that this bacterial system regulates a host cell receptor. The results also suggest that H. pylori uses the DAF receptor as a shield against the immune system, creating an environment of persistent gastric inflammation that makes it easier for more serious disease – like cancer – to develop.

— Melissa Marino

A better model for kidney damage

Acute kidney injury (AKI) – most commonly caused by reduced blood flow or toxic agents – contributes significantly to illness and death among hospitalized patients. The cellular-level mechanisms that underlie AKI are not fully understood. Existing animal models usually rely on a single insult that causes widespread kidney cell death, an influx of inflammatory cells, and vascular injury – features that do not mimic clinical AKI.

Manakan Srichai, M.D., and colleagues have developed a new transgenic mouse model of AKI that limits cell death to a particular part of the kidney – the thick ascending limb. The mice have a severely reduced glomerular filtration rate (a measure of kidney function), reduced ability to concentrate the urine, and visual signs of AKI. The findings in the August Journal of the American Society of Nephrology suggest that targeting damage to select kidney cells in mice produces injury that may more closely resemble AKI in humans, providing a novel model for further studies.

— Leigh MacMillan

Past Aliquots

June 22, 2012
June 8, 2012
May 11, 2012
April 27, 2012
April 13, 2012
March 30, 2012
March 16, 2012