With a $2.5 million grant from the National Heart, Lung, and Blood Institute (NHLBI), researchers at the University of Rochester School of Medicine and Dentistry will study a new way to prevent the damage caused by a heart attack. Keith Nehrke, Ph.D. and Paul S. Brookes, Ph.D. will collaborate on the four-year grant, which focuses on the harm that results from a lack of blood flow to our body’s most vital organ. Without blood to deliver oxygen, heart cells die or don’t function as well as they should.
Coronary heart disease, which includes chest pain and heart attack, is the number one cause of death for both men and women in the United States, according to NHLBI. Currently, other than “plumbing” solutions such as clot-busting drugs, there are no FDA approved drug therapies that physicians can administer before, during or after a heart attack to reduce injury.
“Physicians treat more than half a million heart attacks every year and this number will likely rise with our rapidly aging population,” said Nehrke, an associate professor of Medicine and Pharmacology and Physiology at the medical school. “Our goal is to find a drug target; if you could deliver a drug to prevent heart attack damage that would be a huge step forward.”
Nehrke, Brookes and Cole Haynes, Ph.D., a scientist from Memorial Sloan Kettering Cancer Center, will begin their research in a unique way: by studying a stress surveillance mechanism in a roundworm called C. elegans. Surprisingly, there are many similarities in how worms and mammals deal with stress. Low levels of oxygen – like the heart experiences during chest pain or a heart attack – place major stress on cells.
Haynes discovered the surveillance mechanism (called the “mitochondrial unfolded protein response”), which senses cellular stress and sends a call for help to the nucleus. The nucleus then produces repair molecules called chaperones to rescue the cell from damage.
The team will analyze how this mechanism protects against low oxygen levels (also called ischemia) in worms and identify genes that perform the same functions in mice. Ultimately, they want to understand how this stress response can be altered in mice to protect the heart.
“If we can proactively switch on this surveillance mechanism with a drug, we can trick the cell into thinking that it is under stress. That will prompt the nucleus to make more protective molecules, like chaperones,” said Brookes, an associate professor of Anesthesiology and Pharmacology and Physiology. “If we could do this before a heart attack, we could arm the heart with the tools it needs to combat the damage that’s about to ensue.”
“This is an outstanding project that proposes a new paradigm for reducing injury associated with low oxygen levels and might open up new avenues to treat patients with heart attacks,” said Charles Lowenstein, M.D., chief of Cardiology at UR Medicine’s Strong Memorial Hospital.
The team says that the work is a long way from being applied in patients and acknowledges the challenge of delivering a therapy before a heart attack, since you can’t predict when one will strike. But, they say this early research is essential to identifying new treatment strategies and drug targets for major killers like heart disease.
“You have to understand the underlying mechanisms of the entire disease process before identifying a drug that can modify the process,” noted Nehrke. “Basic research is like learning to build a car, and clinical research is like taking the car to the track to see how fast it is. Without basic research, you have nothing to test.”
This is Nehrke and Brookes’ second collaborative, multiple-principal-investigator NIH grant. They credit team science – working with other researchers with distinct but complementary expertise – for their success, including the publication of more than 10 shared scientific articles from their laboratories over the past 5 years.
Key to securing the current grant was Salvador Peña, an M.D./Ph.D. student in Nehrke’s lab who received a Ruth L. Kirschstein National Research Service Award from the National Institute for General Medical Sciences in 2014 to study the stress surveillance mechanism in worms. Nehrke says Peña’s work was instrumental in generating preliminary data to support their new approach.