Preventing and reversing this disease is still largely a puzzle to scientists working to put all the right pieces into place and form a complete picture of health for millions of patients who suffer its devastating effects worldwide.

So notes a University of Kentucky researcher whose perspective is published in the current issue of Nature. Alan Daugherty, director of the University of Kentucky Cardiovascular Research Center, and Dr. Daniel Rader, an endocrinologist and researcher at the University of Pennsylvania, co-authored the article, which offers insight into the complex process of translating scientific discoveries in the laboratory into new therapies for atherosclerosis.

While advances have been made in understanding how genetics, metabolism of HDL and LDL cholesterol, the inflammatory process, blood clots, and blood pressure regulation all play a part in the atherosclerosis disease process, a solution is likely many years away and will require huge--but worthwhile--investments of time, money and collaboration across fields of study. Decisions remain about which drugs to advance to clinical trials and how to measure the success of those therapies, Daugherty and Rader note.

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"Loss of p22phox affects two enzyme complexes: one in phagocytes that is responsible for the immune defect, and one in the inner ear," Banfi said. "Since this is the first mouse model for defects in the p22phox subunit, this is the first time that its role in balance has been revealed."

Although inner ear cells looked normal in the mutant mice, the researchers discovered that otoconia -- tiny calcium carbonate crystals that are essential for sensing gravity -- do not form in the inner ears of these mice. Restoring the normal gene to the mutant mice rescued otoconial production and prevented the balance disorder. However, although the treatment did improve the mice's immune response, the partial restoration of gene expression was not sufficient to cure the immune deficiency completely.

"This may mean that gene therapy, which would only partially restore expression of p22phox, would not completely cure CGD in humans," cautioned Banfi. "We may have to look for alternatives and these mice will be ideal models to test new ideas for therapy."

The team was also able to track the location of the Nox complex during embryonic development of the inner ear by visualizing the location of p22phox. Interestingly, the complex does not reside in the same place that the otoconia form leading the researchers to propose a new mechanism by which the Nox complex controls production of the crystals.

"We speculate that superoxide radicals generated by the p22phox “containing complex facilitate the formation of otoconia by producing the right conditions, high pH and high calcium concentration, in the compartment where these calcium carbonate crystals form," Banfi explained.

The study was funded in part by grants from the National Institutes of Health.

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