Grant: Operating Grant

Conditions such as hypertension, heart attack or heart valve disease, increase the risk of heart failure. An intermediate step between these conditions and heart failure is cardiac hypertrophy, or abnormal growth of the heart. Finding ways to avert hypertrophy has emerged as a research priority. Our focus is on Peroxisome Proliferator-Activated Receptors (PPARs). Drugs that activate PPARs block hypertrophy. We hypothesize that PPARs protect against hypertrophy by activating an enzyme called diacylglycerol kinase (DGK); DGK then inhibits critical signals that promote hypertrophy. We will study the mechanisms that mediate the ability of PPAR-DGK signaling to inhibit hypertrophy. We will use a well-established model of hypertrophy - rat heart muscle cells that are treated with a growth stimulus. We have identified targets within hypertrophy pathways at which PPAR-DGK signaling might be interfering. The effects of PPAR-DGK signaling on these targets will be pursued by genetic, biochemical, and imaging techniques. We will next determine the effects of PPAR-DGK signaling on hypertrophy in intact animals. We will switch to mice so we can take advantage of relevant genetically-manipulated mice. We will generate hypertrophy in normal mice, and in mice that do not express DGK or PPARs, by placing a band on the aorta. We will treat mice with PPAR-activating drugs and assess PPAR-DGK signaling. There is major interest in regulation of cardiovascular function by PPARs. PPARs act directly on heart muscle cells to block hypertrophy, and we know that DGK is important in this process. We will be the first to study how PPAR-DGK signaling ultimately blocks cardiac hypertrophy. The incidence of heart failure is predicted to double by 2025, so we are striving to block the transition from hypertrophy to heart failure. By learning how PPARs control this transition, we may discover molecular targets that can be manipulated for therapeutic gain to treat heart disease.