Islets of youth  pg. 5

-- When one of the two copies of the pdx1 gene normally inherited from one’s parents is inactivated in mice, the animals exhibit a pre-diabetic state in which blood glucose levels are higher than normal. Similarly, in humans, certain mutations in the gene are associated with increased risk for developing a form of type 2 diabetes.

-- Both pdx1 and another regulatory gene for pancreas specific transcription factor-1a (Ptf1a) signal progenitor cells to become pancreas. When Ptf1a is inactivated, however, these cells instead form the lining of the duodenum.

Two other transcription factors -- HNF6 and FoxM1 – studied by Gannon and her colleagues play important roles in development and maintenance of pancreatic function.

HNF6’s role is time sensitive: unless its gene is turned off at a critical stage, the pancreatic islets fail to develop normally in mice. FoxM1, on the other hand, is essential for expanding the population of insulin-producing beta cells after birth. Mice lacking the FoxM1 gene are born with normal pancreases but slowly lose beta cells and end up with diabetes.

These factors “are all connected, but we haven’t filled in all the lines,” says Gannon, associate professor of Medicine, Molecular Physiology & Biophysics, and Cell & Developmental Biology.

Brand new view

Meanwhile, Magnuson had become interested in a variation of the knock-out technique that uses a DNA-cutting enzyme called Cre recombinase.

Because the enzyme cuts at precise locations in the DNA, this method enabled Magnuson and his colleagues to inactivate various genes involved in insulin action and glucose regulation in specific tissues, notably the pancreas and liver – to figure out exactly what they do. A major goal now is to learn all the steps needed to direct a stem cell to become a beta cell.

Wright visualizes a day when scientists will be able to create “personalized” pluripotent stem cells from the tissues of a patient with diabetes, and then kick them forward to see if they develop into beta cells completely normally, or display abnormalities at a specific stage of formation.

“That is what stem cell biology has done for us so far,” adds Magnuson, the Earl W. Sutherland Jr. Professor of Molecular Physiology & Biophysics. “It has given us a brand new view of what is possible.”

It also has spurred collaboration across diverse research disciplines.

For example, Vanderbilt scientists as diverse as David Piston, Ph.D., who helped pioneer the use of fluorescence imaging to study living beta cells, Richard O’Brien, Ph.D., who studies diabetes-related genes, and Guoqiang Gu, Ph.D., an expert on Cre recombinase, compare notes with Powers, Magnuson, Wright, Gannon, Stein and their colleagues in a weekly Beta Cell Biology Interest Group.

On a regional level, Stein recently organized the first annual meeting of the Upper Midwest Islet Club at Vanderbilt to foster communication between senior and junior investigators, with “a decided focus” on graduate students, post-doctoral fellows and new faculty members. The goal: to inspire the next generation of researchers.

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