Ottolia Receives Grant to Study Cardiac Acidosis
Michela Ottolia, PhD, associate professor at the Cedars-Sinai Heart Institute, has received a two-year, $140,000 grant from the American Heart Association to study how changes in blood acidity affect heart function.
Acidosis, or increased acidity in the blood, may occur in patients with lung or kidney diseases and during a heart attack or cardiac arrest. If not properly treated, this condition may cause a slow, irregular heartbeat and dangerously low blood pressure. Present therapies for acidosis are limited.
Ottolia, principal investigator on the study, will seek to discover how acidosis may alter the function of a protein called the sodium-calcium exchanger, which is responsible for maintaining optimal calcium levels in heart cells. Since calcium is essential for proper heart function, abnormal sodium-calcium exchanger activity potentially may lead to heart damage.
"We hypothesize that the activity of the sodium-calcium exchanger is severely impaired when heart cells become acidic, which then contributes to life-threatening conditions such as weak and irregular heartbeats," said Ottolia. "Our studies will determine if the sodium-calcium exchanger is involved in the damaging effects of high blood acidity, potentially paving the way for new therapeutic options."
The research is being conducted in collaboration with Joshua Goldhaber, MD, director of basic research programs at the Heart Institute and associate director of the coronary intensive care unit at Cedars-Sinai.
Ottolia and colleagues will induce acidosis and examine its effects in heart and cardiac cells isolated from normal mice or genetically altered mouse models in which the sodium-calcium exchanger has been removed from the heart. By comparing the effects of acidosis in normal and genetically manipulated mice, the researchers hope to better understand the role of the sodium-calcium exchanger in this condition.
In addition, the researchers have been able to identify the amino acids of the sodium-calcium exchanger protein that are responsible for sensing changes in pH levels, or acidity. Ottolia plans to replace the sodium-calcium exchanger in mouse cardiac cells with designer exchanger lacking sensitivity to changes in pH to determine the relevance of this regulation in heart function.
"The goal of the research is to provide useful insights on the molecular mechanisms that underlie this pathology, ultimately leading to the development of more efficient treatments," said Ottolia.
Photo (top): Michela Ottolia, PhD
Image (bottom): This model shows the structure of the sodium-calcium exchanger, a protein important for cardiac functioning. Highlighted are the exchanger's transmembrane segments (green helixes in the plasma membrane); the Na-regulatory domain (Na-RD), responsible for sensing intracellular sodium; and two regions (Ca-RDs) that sense changes in calcium (yellow sphere) within the cytoplasm.