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Transformative award from NIH supports research on malleable cells

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Quinn Eastman

The National Institutes of Health has announced a five-year, $1.9 million Transformative Research Award to Emory virologist Edward Mocarski, PhD for his work on how the mechanisms of programmed cell death can be subverted.

Mocarski is Robert W. Woodruff professor of microbiology and immunology at Emory University School of Medicine and Emory Vaccine Center. His research, which originated in probing how cells commit suicide when taken over by viruses, could lead to advances in regenerative medicine and organ transplant.

The grant, funded through the National Institute of Allergy and Infectious Diseases, is one of nine "high-risk, high-reward" Transformative Research Awards announced by the NIH (13 recipients) on October 6.

The Transformative Research Award program, established in 2009, supports "exceptionally innovative, unconventional, paradigm-shifting research projects that are inherently risky and untested."

"This Transformative award was made possible because of the creative and engaged graduate students and postdoctoral fellows I have had working with me at Emory," Mocarski says.

Mocarski, working with former graduate student William Kaiser, PhD and Emory geneticist Tamara Caspary, PhD, showed that two complementary forms of programmed cell death, necrosis and apoptosis, can be genetically excised from mice, leaving a viable animal with a functioning immune system. Kaiser is now at the University of Texas Health Sciences Center in San Antonio.

"We discovered an interlinked system that evolved in host defense against infections that also predisposes to tissue damage and inflammatory disease," Mocarski says. "These programmed cell death pathways also undermine tissue repair, engraftment and nuclear reprogramming of somatic cells."

These findings are yielding additional fruit. Mocarski’s research indicates that cells from these genetically altered mice are unexpectedly malleable, in that they are easier to reprogram into induced pluripotent stem cells. Once reprogrammed, induced pluripotent stem cells (iPS cells) can be directed to become cells of almost any tissue, making them promising potential tools for the treatment of many diseases.

The genetically altered mice are also less susceptible to deadly inflammation and more readily accept bone marrow transplants. The Transformative project’s aims are to exploit these findings and test the ability of drugs that interfere with programmed cell death to facilitate tissue regeneration, iPS cell reprogramming and transplant.

"Eliminating cell death by either genetic or transient small molecule therapeutic means will enhance engraftment, reprogramming and regenerative medicine, with dramatic impact on current and future medical practice," Mocarski says.

The proposal was developed in collaboration with Emory colleagues Edmund Waller, MD, PhD and Mandy Ford, PhD, as well as colleagues from Stanford, Houston Methodist Research Institute and GlaxoSmithKline, Mocarski says.

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