Transformative scientific discoveries don’t happen in a vacuum—they are built on a foundation of basic research. That is the focus of The G. Harold and Leila Y. Mathers Charitable Foundation, which recently awarded two Dana-Farber investigators $1.5 million to fund their research on unraveling the inner workings of human cells.
Edward Chouchani, PhD, is studying the function of lactate in cell proliferation. He has shown that it is a multifunctional signaling molecule playing a key role in controlling that process by binding to and inhibiting SENP1, a critical protein. For almost a century, lactate was thought to be an inert byproduct of glycolysis, one of the ways cells produce energy as they grow and divide. But Chouchani’s lab has discovered that lactate directly inhibits SENP1, with broad implications in cell biology and human physiology.
“I want to establish, for the first time, the mechanistic basis for how lactate is used as a general metabolic signal to control cellular function and cell states,” Chouchani said. “I expect these findings will prove highly relevant to cancer as well as several other areas of biomedicine.”
The foundation is also supporting the work of A. Thomas Look, MD, a pediatric oncologist at Dana-Farber. Look is investigating two tumor suppressor genes—Tet2 and Dnmt3a—found in leukemia and preleukemia syndromes. The proteins encoded by these genes control how the expression levels of many human genes are switched on and off. When Tet2 or Dnmt3a are inactivated by mutated blood cells, they can cause a condition known as clonal hematopoiesis of indeterminate potential (CHIP), which is an overgrowth of mutated cells in the blood. People with CHIP have an increased risk of leukemia, cardiovascular disease, and autoimmune diseases. There is no known treatment for the condition.
Look and his colleagues will analyze the gene expression and characteristics of individual cells to understand how the mutant cells become dominant and why they trigger inflammation. They will
also investigate whether changes of gene expression in mutant blood cells make them vulnerable to certain drugs that can specifically target and kill them without affecting normal blood cells.
“In previous work, we have identified some promising FDA-approved drugs that selectively killed the mutant blood cells,” Look explained. “Because of the generous funding from The Mathers Foundation, we will be able to test the efficacy of these compounds in laboratory models of CHIP. We will also gather important evidence to help us design early stage clinical trials aimed at reducing adverse outcomes for high-risk patients with CHIP.”
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