Genes Differentially Expressed During Heart Failure

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DESCRIPTION (provided by applicant): The American Heart Association estimated the cost of cardiovascular disease in the United States in 2000 to be at $326.6 billion. This figure includes health expenditures and lost productivity resulting from morbidity and mortality. Heart failure is not a disease of the elderly or persons who live unhealthy lifestyles. The highest incidence occurs between 25-45 years of age. Although more patients are surviving their first myocardial infarction, they go on to develop progressive left ventricular dysfunction and end-stage heart failure. As a result, the incidence of congestive heart failure is increasing. Changes in gene expression profiles between normal tissue and diseased tissue can lead to identification of novel drug targets and to the development of drugs that will be able to interfere with disease development. Our hypothesis is that altered gene expression is the basis of the structural and functional changes that accompany the development of heart disease and that changes in gene expression profiles are important indicators of specific disease stages of heart failure. We predict that changes in the expression profile of a critical set of genes will be important indicators and diagnostic markers of heart disease. We have found that about 30 percent of the genes identified in our differential screening have no informative similarity to known genes in any of the public databases. These genes are excellent candidates as drug targets and/or as possible diagnostic markers. Our specific aims are 1) To fully characterize selected genes based on their differential expression in heart failure; 2) To validate the potential targets identified in Phase 1 and prioritize these gene targets; 3) To determine if the levels of the corresponding gene products (proteins) have changed in a manner similar to the change in RNA levels; 4) To link information on the differences in gene expression and protein levels with consequences in cardiac myocytes and muscle strips by using adenoviral vectors to infect myocytes with transgenes that are over-expressed or knocked down (i.e., antisense); 5) To determine if changes in the gene expression pattern that we have identified in the turkey model are also present in the hearts of human patients with end-stage heart failure; 6) To produce the first "human heart failure chip"; 7) To patent novel therapeutic targets that have been identified and validated