Dario Vitturi, Ph.D., an assistant professor in the Division of Molecular and Cellular Pathology, has been awarded $1.8 million in grant funding from the National Institutes of Health’s (NIH) National Institute of General Medical Sciences (NIGMS), for his study of, “Formation, metabolism and cell signaling actions of tryptophan catabolism-derived electrophiles.” The five-year award will run through May 2029.
More than 90 percent of tryptophan (Trp), an essential amino acid that humans obtain through diet, is utilized by the kynurenine (KYN) pathway primarily in the liver. However, this process also has important pathophysiological roles in the brain, kidneys and heart, as well as in modulating immunity, tumor microenvironments and pregnancy. Altered KYN metabolism takes place in aging, cardiovascular disease, organ injury, cancer, and transplantation, where it often is a strong predictor of outcome. However, despite their relevance, the mechanisms behind the effects resulting from changes in systemic and local KYN metabolism are poorly defined. Vitturi’s group has found that Trp metabolism results in the formation of a family of unknown products that can regulate cellular function by attaching to critical proteins.
“We are studying this process because it can redefine our understanding of tryptophan metabolism and have wide-ranging implications across different systems,” Vitturi says. “We want to understand how this new pathway works, how it’s regulated, and what effects it has on key cellular processes. Our hypothesis is that the formation of these reactive products is an endogenous response [of internal origin] that allows cells to adapt to changing environments.”
Vitturi will explore a novel series of endogenous products such as kynurenine-carboxyketoalkene (Kyn‑CKA) that have the potential to modulate cellular and systemic responses. Understanding the formation and regulation of these products will not only provide new insights into the biological actions of an essential nutrient, but it will also have the potential to open new avenues for the development of therapies aimed at improving conditions in which tryptophan metabolism is dysregulated.
“These are exciting times for tryptophan metabolism research. The kynurenine pathway has established itself as a critical pathophysiological hub with implications ranging from cancer to transplant rejection and even to COVID-19 mortality,” Vitturi says. “We have potentially discovered a new branch of tryptophan metabolism that results in the formation of a family of potent bioactive products. When we understand the mechanisms that regulate this new pathway and their impact on cellular function, we can look for new therapeutic strategies.”
Originally from Montevideo, Uruguay, Vitturi obtained his Ph.D. at the University of Alabama at Birmingham in 2010 under the direction of Rakesh Patel, Ph.D., Victor Darley-Usmar, Ph.D., Endowed Professor and Director of the Division of Molecular and Cellular Pathology. Upon completion of his graduate studies, Vitturi joined the Department of Pharmacology and Chemical Biology at the University of Pittsburgh, first as a postdoctoral associate, and then as a faculty member. In August 2022 he returned to UAB as an assistant professor in the division where he completed graduate studies.