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费用为3266亿美元。这一数字包括卫生支出和因发病率和死亡率而造成的生产力损失。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。虽然更多的患者在首次心肌梗死后存活，但他们继续发展为进行性左心室功能障碍和终末期心力衰竭。因此，充血性心力衰竭的发病率正在增加。正常组织和患病组织之间基因表达谱的变化可以导致新的药物靶点的鉴定和能够干扰疾病发展的药物的开发。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志物。我们发现，在我们的差异筛选中发现的基因中，约有30%与任何公共数据库中的已知基因没有信息相似性。这些基因是作为药物靶点和/或作为可能的诊断标记物的优秀候选者。 我们的具体目标是：1）充分表征基于心力衰竭中差异表达的所选基因; 2）验证第1阶段中鉴定的潜在靶点并优先考虑这些基因靶点; 3）确定相应基因产物的水平是否与心力衰竭的发生有关。（蛋白质）以类似于RNA水平变化的方式发生变化; 4）通过使用腺病毒载体用过表达或敲低的转基因感染心肌细胞（即，反义）; 5）确定我们在火鸡模型中发现的基因表达模式的变化是否也存在于患有终末期心力衰竭的人类患者的心脏中; 6）生产第一个“人类心力衰竭芯片”; 7）为已经确定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