The Molecular Basis of Cardiac Senescence

心脏衰老的分子基础

• 批准号: 7131115
• 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/7131115
• 关键词: aging; biopsy; cell senescence; functional /structural genomics; gene expression; genetic regulation; heart ventricle; human tissue; microarray technology; myocardium; polymerase chain reaction; serial analysis of gene expression

The Laboratory of Cardiovascular Science has a strong commitment to the study of aging myocardium. To identify gene products in heart potentially involved in aging, functional genomic analyses (cDNA microarrays and Serial Analysis of Gene Expression) have been employed to analyze mRNA from left ventricles of Fisher 344 rats with or without caloric restriction, Wistar rats, C57Bl/6 mice during the perinatal period and with aging, CBA mice treated with biopeptides implicated in gerontoprotection, and human biopsies from failing and non-failing myocardium. The aim of these projects are to determine which gene products are regulated as a function of age or disease, and then use independent methods to determine the underlying mechanisms responsible for the altered changes in gene expression. In 2002, we published a reference dataset (SAGE analysis) of the mouse myocardium that is publicly available, and we have expanded these studies to examine male versus female mice and young versus old mice. We have completed a large-scale transcriptome analysis of an aging Fisher 344 aging rat model and compared these results with other rodent strains. We are completing an extensive quantitative-PCR analysis to validate these data, and by independent techniques, to determine the significance of the changes in gene expression with the aging process. We have expanded our aging studies in rodent to include in vitro analyses of cultured cardiomyoyctes and fibroblasts to delineate mechanisms underlying the aging response of cardiac genes, and are in the process of elucidating genetic correlates underlying these changes in transcript abundance. Finally, we have employed functional genomic techniques (microarrays) to examine the transcriptomes of LVs from failing (n=8) and non-failing human myocardium (n=7). Following identification of a pool of HF-responsive candidate genes by microarrays and statistical methods, we employed Q-PCR on a larger sample population (n=34) to validate and examine the role of contributing biological variables (age and gender). We find that most of the HF-candidate genes (including transcription factors, modifying enzymes, ECM proteins and metabolic enzymes) demonstrated significant changes in gene expression; however, the majority of the putative changes depended on variables such as sex and age, and not on HF alone. Additionally, some putative HF-responsive gene products demonstrated highly significant changes in expression as a function of age and/or sex, but independent of HF. These studies with human samples have now expanded to include hypertension, and we have begun a meta analysis of human heart failure data. The data from each of these projects are being compared in an effort to identify and analyze the function of candidate genes in aging and disease.

心血管科学实验室对衰老心肌的研究有着坚定的承诺。 To identify gene products in heart potentially involved in aging, functional genomic analyses (cDNA microarrays and Serial Analysis of Gene Expression) have been employed to analyze mRNA from left ventricles of Fisher 344 rats with or without caloric restriction, Wistar rats, C57Bl/6 mice during the perinatal period and with aging, CBA mice treated with biopeptides implicated in gerontoprotection, and human活检失败和非击败心肌。这些项目的目的是确定哪些基因产物受年龄或疾病的函数调节，然后使用独立的方法来确定导致基因表达变化改变的基本机制。 2002年，我们发布了公开可用的小鼠心肌的参考数据集（SAGE分析），并扩大了这些研究，以检查雄性小鼠与雌性小鼠与老鼠的雄性小鼠。 我们已经完成了老化Fisher 344老化大鼠模型的大规模转录组分析，并将这些结果与其他啮齿动物菌株进行了比较。我们正在完成广泛的定量PCR分析，以验证这些数据，并通过独立的技术来确定基因表达变化与衰老过程的重要性。我们已经扩大了啮齿动物的衰老研究，以包括对培养的心肌细胞和成纤维细胞的体外分析，以描述心脏基因衰老反应的基础机制，并正在阐明在转录丰度中这些变化的基本相关性的遗传相关性。 最后，我们采用了功能性基因组技术（微阵列）来检查失败（n = 8）和未释放人类心肌（n = 7）的LVS转录组。通过微阵列和统计方法鉴定出HF响应性候选基因库后，我们对较大的样本人群（n = 34）采用Q-PCR来验证和检查贡献生物学变量（年龄和性别）的作用。我们发现，大多数HF候选基因（包括转录因子，修饰酶，ECM蛋白质和代谢酶）的基因表达发生了显着变化。但是，大多数推定的变化取决于变量，例如性别和年龄，而不是单独使用HF。此外，一些推定的HF响应基因产物表现出表达的显着变化，这是年龄和/或性别的函数，但与HF无关。这些对人类样本的研究现在已经扩展到包括高血压，我们已经开始对人体心力衰竭数据进行元分析。比较了这些项目中每个项目的数据，以识别和分析候选基因在衰老和疾病中的功能。