Project 453163

As some people age the heart becomes less efficient in pumping blood out of the ventricles and fills with blood to dilate like a balloon. This defect may also be observed and accelerated if the heart is stressed or is subjected to cancer therapy such as seen in patients on chemotherapeutic agents. In fact a large number of cancer patients die from heart disease known as dilated cardiomyopathy or the balloon heart induced by certain cancer drugs. In addition, susceptibility to chemo treatment and heart disease is sex related. We have discovered a new pathway that can control the genes involved in causing the dilated heart syndrome. In fact we have found a gene therapy (its like a drug) that can prevent the damage that chemotherapeutic drugs induce in the cells that make up the heart muscle. This gene therapy can also help heart cells survive better in response to stress. These studies were conducted in cells isolated `from the mouse heart. We propose to use the gene therapy in animal models of stress and drug induced dilated heart disease to examine its use as a treatment to prevent the balloon heart syndrome. Old age, stress and drugs used to treat cancer can lead to dilated heart disease and there is no treatment. It is notable that in about 35% of patients exhibiting dilated heart disease , the cause remains unknown. For the first time, our results identify that the deregulation of the E2F pathway leads to this disease by influencing energy utilization and receiving/collating essential information in the heart cells. Our data points to new mechanisms that lead to dilated hearts. Here we propose studies to further interrogate these new mechanisms that will pave the way to potentially treating this fatal disease through discovery science as detailed in our research program