Researchers at the University of Kentucky College of Allied Health Professions and the UK College of Pharmacy recently received a four-year grant of $1,142,326 from the National Institute of Neurological Disorders and Stroke, part of the National Institutes of Health, to examine the role the molecule cyclic ADP-ribose (cADPR) plays in signaling pathways leading to cell death.
"Cyclic ADP-ribose is an exciting new lead in the area of cellular signaling," said Myron Jacobson, Ph.D., professor, UK College of Pharmacy, and faculty affiliate of UK's Advanced Science and Technology Commercialization Center (ASTeCC). "Our pilot data show that it is involved in cell responses to damage that occurs in heart attack, stroke and neurodegenerative diseases and possibly in the development of cancer."
When the DNA in a cell is damaged, a complex set of cellular signaling pathways begins. These pathways can lead to repair of the damage, programmed cell death (apoptosis), or cell death accompanied by inflammation (necrosis).
Many major diseases involve these signaling pathways either through not enough activation of the pathways, as in cancer, or too much activation, as in heart attack and stroke.
A disruption in the regulation of calcium ions can lead to apoptosis, particularly with oxidative stress, or cell damage caused by molecules that are highly reactive forms of oxygen such as free radicals and peroxides. This coupled with the discovery, about 10 years ago, that cADPR is involved in the regulation of calcium ions, led the Jacobson research team to hypothesize that cADPR may be a key component in cell death, particularly in those situations involving oxidative stress, such as heart attack and stroke.
The research team, led by Jacobson and Elaine Jacobson, Ph.D., professor, Department of Clinical Sciences, UK College of Allied Health Professions, member of the UK Markey Cancer Center, and faculty affiliate of ASTeCC, plans to determine the structure of specific proteins that synthesize cADPR and where those proteins are located in cells. Once the structures of the proteins are identified, molecules that can either assist or hinder their activity can be identified.
"Our long-term goals are to identify and relate the signaling pathways to understand better the consequences of their activation," Elaine Jacobson said. "With this data new therapeutic agents can be developed."