Team Uses RNAi to Target Diabetes, Obesity

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Two papers published in January by a team of researchers at the University of Massachusetts Medical School (UMMS) report finding proteins that regulate insulin sensitivity and the ability of cells to burn fat. The proteins were identified using a new testing process the UMMS team developed based on RNA-interference to selectively silence genes. The proteins were found to be integral to the mechanisms that allow cells to process insulin, absorb sugar and promote the build up or the burning of fatty tissues.

“The findings in these papers give us a better understanding of the biological links between obesity and type 2 diabetes. And the proteins we’ve identified as new potential drug targets may have profound implications for the treatment of these two conditions,” said Michael P. Czech, PhD, professor and chair of molecular medicine and professor of biochemistry & molecular pharmacology, who led the research efforts. “Another important advance we report here is the high-throughput screening assay we’ve developed using RNAi-this new technology allows us to greatly accelerate our research.”

The results of Dr. Czech’s studies are detailed in the paper “An RNAi-based screen identifies MAP4K4/NIK as a negative regulator...” published on-line January 30 by the Proceedings of the National Academy of Sciences (PNAS) and “Suppression of oxidative metabolism and mitochondrial biogenesis by RIP 140...” published in the January edition of The Journal of Clinical Investigation, (JCI) co-authored by researchers at the Imperial College of London who collaborated with Czech’s team.

In the PNAS paper, the researchers found the protein MAP4K4/NIK is a negative regulator of a fat cell’s ability to react to insulin and take sugar out of the bloodstream. In other words, the more MAP4K4/NIK present in fat cells, the less able the fat cells are to take up sugar in response to insulin. The loss of insulin sensitivity in fat and muscle cells is a major factor in the onset of type 2 diabetes. “This protein is in the family called kinases, which is important because kinases are drugable—we already know how to design drugs that work to block kinases,” Czech said. “So if a drug can be developed to block this kinase, insulin sensitivity may be increased and the symptoms of type 2 diabetes may be decreased.”

In the JCI paper, Czech and colleagues found a protein called RIP 140 is also a negative regulator of insulin sensitivity, but also, remarkably, regulates the ability of cells to burn off fat and covert it to energy. “Our results suggest that RIP 140 may be a therapeutic target for the syndromes of obesity and type 2 diabetes,” the authors concluded in the paper. To further validate the results regarding RIP 140 in cell cultures, the team at Imperial College developed a mouse model designed without the gene that expresses RIP 140. The mice without RIP 140 resisted weight gain, even when fed a high-fat diet, and were shown to have better insulin sensitivity and better glucose tolerance than the mice with RIP 140 present. “The in vivo data are very encouraging,” Czech said. “There is more work to be done, but we believe this is a very promising target.”

The work published in both papers was based, in large part, on the data generated by a novel 96-well screening assay Czech’s lab developed which uses RNAi to screen for proteins. Hailed as one of the most important biomedical research developments in decades, RNAi is a biological process that prevents genes from making proteins. It was discovered in 1998 by UMMS’s Craig C. Mello, PhD, the Blais University Chair in Molecular Medicine and Howard Hughes Medical Institute Investigator, and colleague Andrew Fire, PhD, now of Stanford University. Since Mello and Fire’s seminal publication, RNAi has been widely adopted as the key to unlock the secrets of the human genome. Czech’s lab created a high-throughput 96-well screening tool which uses RNA-i technology for the rapid analysis of proteins in fat cells. “With this assay, in a matter of weeks we can answer questions that before would have taken us years,” Czech said. “The incredible acceleration of research has allowed to identify these proteins as important drug targets.”

The patent rights that cover Czech’s assay for identifying new drug targets, and the indication of RIP 140 as a drug target for obesity and type 2 diabetes, have been exclusively licensed by Cytrx Corp. of Los Angeles.

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