Proteins Implicated In Cardiac Senescence

与心脏衰老有关的蛋白质

• 批准号: 6508399
• 负责人: Kenneth R Boheler
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6508399
• 关键词: aging; cardiac myocytes; cell senescence; developmental genetics; gene expression; laboratory rat; microarray technology; muscle proteins; myocardium

The Laboratory of Cardiovascular Science has a strong commitment to identifying and studying the process of aging in the myocardium. To identify gene products in heart potentially involved in aging, cDNA microarrays were analyzed with mRNA from left ventricles of Fisher 344 rats. Samples from 12, 18, 24 and 30 months were compared with those from 6 months. Of over 9000 unique cDNAs analyzed as a function of age, 388 (4.3%) showed altered expresson where the balanced differential expression (BDE) was greater than 2.0 (down-regulated) or less than -2.0 (up-regulated). Of the 388 sequences, 125 were unknown ESTs. The number of transcripts with altered abundances generally increased with aging and were as follows: 12 mo. 1 increased (I) and 2 decreased (D); 18 mo. 29 (I), 75 (D); 24 mo. 37 (I), 33 (D); and 30 mo. 182 (I), 67 (D). Of the 388 transcripts with altered abundance, 91% showed changes in expression at one time point, and only 9% showed changes in more than two age groups. Most of the RNAs showing altered expression at multiple time points have been grouped into functional categories. The data indicate that the vast majority of transcripts (greater than 95%) do not change with aging. Only 4.3% of the transcripts showed age-dependent alterations, most of which occurred late in life (64%, 249/388 occurred at 30 months). Of these, 47% (118/249) corresponded to ESTs whose identity remain to be determined. We have now completed an extensive quantitative-PCR analysis to identify gene products whose expression is altered in aging and eliminated numerous false positives. Now that the initial screening has been completed, the aim is to determine the significance of the changes in gene expression with the aging process. For this, molecular analyses are underway to identify which products may actually be involved in the hypothesized signal events responsible for the aging process. As a corollary to this project, we have begun and are near completion of an additional microarray analysis of human control and failing hearts. The data are being compared with that generated in the aging model to identify candidate genes implicated not only in aging, but also in disease.

心血管科学实验室致力于识别和研究心肌的衰老过程。为了鉴定心脏中可能与衰老相关的基因产物，用来自 Fisher 344 大鼠左心室的 mRNA 分析了 cDNA 微阵列。将 12、18、24 和 30 个月的样本与 6 个月的样本进行比较。在作为年龄函数进行分析的 9000 多个独特 cDNA 中，有 388 个 (4.3%) 显示出表达改变，其中平衡差异表达 (BDE) 大于 2.0（下调）或小于 -2.0（上调）。在 388 个序列中，125 个是未知的 EST。丰度改变的转录本数量通常随着年龄的增长而增加，如下：12个月。 1 增加 (I)，2 减少 (D)； 18个月。 29（一）、75（丁）； 24 个月37（一）、33（丁）；和 30 个月。 182（一）、67（丁）。在 388 个丰度发生改变的转录本中，91% 在一个时间点表现出表达变化，只有 9% 在两个以上年龄组表现出变化。大多数在多个时间点表现出表达改变的 RNA 已被分为功能类别。数据表明，绝大多数转录本（大于 95%）不会随着衰老而改变。只有 4.3% 的转录本显示出年龄依赖性改变，其中大多数发生在生命后期（64%，249/388 发生在 30 个月大时）。其中，47% (118/249) 对应于其身份仍有待确定的 EST。我们现在已经完成了广泛的定量 PCR 分析，以鉴定其表达在衰老过程中发生改变的基因产物，并消除了许多假阳性。现在初步筛选已经完成，目的是确定基因表达变化随衰老过程的意义。为此，正在进行分子分析，以确定哪些产品实际上可能参与了导致衰老过程的假设信号事件。作为该项目的必然结果，我们已经开始并即将完成对人类控制和衰竭心脏的额外微阵列分析。将这些数据与衰老模型中生成的数据进行比较，以确定不仅与衰老有关而且与疾病有关的候选基因。