Genes Differentially Expressed During Heart Failure

描述(由申请人提供)：美国心脏协会估计，2000年美国心血管疾病的成本为3266亿美元。这一数字包括保健支出以及因发病率和死亡率造成的生产力损失。心力衰竭不是老年人或生活方式不健康的人的疾病。发病率最高的年龄段为25-45岁。虽然更多的患者在第一次心肌梗死中存活下来，但他们继续发展为进行性左心功能不全和终末期心力衰竭。因此，充血性心力衰竭的发生率正在增加。正常组织和疾病组织之间基因表达谱的变化可以导致识别新的药物靶点，并开发能够干预疾病发展的药物。我们的假设是，基因表达的改变是伴随心脏病发展的结构和功能变化的基础，基因表达谱的变化是心力衰竭特定疾病阶段的重要指标。我们预测，一组关键基因表达谱的变化将成为心脏病的重要指标和诊断标记。我们发现，在我们的差异筛选中发现的大约30%的基因与任何公共数据库中的已知基因都没有提供信息的相似性。这些基因是很好的候选药物靶点和/或可能的诊断标记。 我们的具体目标是：1)根据心力衰竭中基因的差异表达，对选定的基因进行充分的表征；2)验证在第一阶段确定的潜在靶点，并优先考虑这些基因靶点；3)确定相应基因产物(蛋白质)的水平是否以类似于RNA水平的变化的方式发生变化；4)通过使用腺病毒载体将过度表达或下调(即反义)的转基因感染心肌细胞，将基因表达和蛋白质水平的差异与心肌细胞和肌条中的后果联系起来；5)确定我们在土耳其模型中发现的基因表达模式的变化是否也存在于人类终末期心力衰竭患者的心脏中；6)生产第一个“人类心力衰竭芯片”；7)为已被识别和验证的新型治疗靶点申请专利。

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