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April 2011

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Jetten to investigate a novel stem cell treatment for diabetes

By Eddy Ball
April 2011

Anton Jetten, Ph.D.

Jetten's research has been focusing on the study of several nuclear proteins, including retinoic acid orphan receptors (RORs). Investigations of the role of RORs led him into the discovery of Glis proteins and their role in diabetes and kidney disease. (Photo courtesy of Steve McCaw)

NIH announced Feb. 25 supplemental support of $86,000 in fiscal year 2011 for an innovative research project headed by NIEHS cell biologist Anton Jetten, Ph.D. The award of NIH Common Fund money through the new NIH Center for Regenerative Medicine (NCRM)(http://commonfund.nih.gov/stemcells/) Exit NIEHS will support investigation into the role of transcriptional regulator Gli-similar (Glis) 1-3 proteins in the generation of pancreatic beta cells from induced pluripotent stem (iPS) cells, as part of the development of an innovative therapy for the treatment of patients with diabetes.

As Jetten's proposal explains, the prevention and effective treatment of diabetes is a major public health priority. Currently, 10 percent of U.S. adults have diabetes at an estimated annual cost of $174 billion, with the incidence expected to rise to as high as 33 percent of the adult population by 2050.

Although state-of-the-art insulin therapy can save lives and benefit patients with adult-onset diabetes, the therapy does not prevent long-term complications. Diabetes can lead to adult blindness, kidney failure, and limb amputation, or to related conditions, cardiovascular disease and stroke, which are chronic diseases that are also on the rise.

Targeting repression and transcription of genes involved in insulin production

Jetten(http://www.niehs.nih.gov/research/atniehs/labs/lrb/cell-bio/index.cfm), who serves as the chief of the NIEHS Laboratory of Respiratory Biology (LRB) and principal investigator of the LRB Cell Biology Group, is building on prior research with Glis3 knockout mice. In those experiments, he and his group found that null mice lack pancreatic beta cells, the natural source of insulin, and develop neonatal diabetes, hypothyroidism, and polycystic kidney disease over the course of their lives.

Glis and Gli proteins bind specific DNA elements-known as Gli-response elements (GRE)-in the promoter of target genes and can function as activators or repressors of transcription. Studies performed by the Cell Biology Group have demonstrated that Glis genes are expressed in a temporal and spatial manner during development, suggesting that they are important in the regulation of several developmental processes.

As Jetten noted in his proposal, "Genetic studies [have also] linked mutations within the Glis3 gene to increased susceptibility to type 1 and type 2 diabetes in humans," paralleling findings in animals on the critical importance of Glis3 in diabetes. "Glis3," Jetton explained, "has a dual role in regulating both the development and maintenance of mature beta cells."

Investigating a potential stem cell therapy for diabetes

Jetten pointed to new technologies for reprogramming adult cells to an induced pluripotent state for generating iPS cells from an individual's readily accessible skin or blood cells. Reprogramming adult cells into insulin-producing beta cells offers an alternative to human embryonic stem cell approaches, and it also eliminates the need for immunosuppressive therapies.

The proposal outlines an elegant series of experiments to test protocols for inducing differentiation in iPS cells, and to determine whether Glis3 might provide a new target for managing diabetes in a therapy designed to produce cells capable of maintaining near-normal regulation of blood sugar.

NCRM is serving as a stem cell resource for the research community. As part of its award, the Center will perform an interim review of Jetten's project to determine continued funding for fiscal year 2012.

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