Transcription Regulation in the Aging Heart

衰老心脏中的转录调控

• 批准号: 7848720
• 负责人: JEANNE Y WEI
• 金额: $ 7.92万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7848720
• 关键词: Address; Adrenergic Agents; Adult; Age; Aging; Aging-Related Process; Animals; Apoptosis; Binding; Binding Proteins; Birth; Calcium; Calsequestrin; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Line; Cells; Cessation of life; Complex; DNA Binding Domain; Data; Development; Doctor of Medicine; Doctor of Philosophy; Dominant-Negative Mutation; Doxycycline; Echocardiography; Elderly; FOS gene; Future; Gene Expression; Gene Targeting; Genes; Growth and Development function; Heart; Histology; Human; Hypertrophy; Impairment; In Vitro; Investigation; Isoproterenol; Link; Longevity; Maintenance; Mediating; Messenger RNA; Methods; Molecular Profiling; Morbidity - disease rate; Mus; Muscle; Mutation; Myocardial; Necrosis; Neonatal; Newborn Infant; Pattern; Performance; Phenotype; Principal Investigator; Process; Promoter Regions; Protein Binding; Protein Biosynthesis; Protein Isoforms; Proteins; Rattus; Regulation; Rodent; SERCA2a; Serum Response Element; Serum Response Factor; Signal Transduction; Sodium-Calcium Exchanger; Stress; Structure; System; Testing; Tetracyclines; Transcriptional Regulation; Transgenic Mice; Transgenic Model; Ventricular; adrenergic; age related; aged; aging gene; base; cofactor; comparative; healthy aging; in vivo; insight; interest; mortality; mouse model; mutant; normal aging; novel; overexpression; postnatal; programs; protein expression; response; transcription factor; young adult

DESCRIPTION (provided by applicant): This revised application seeks support to investigate the basic mechanisms of aging in the heart. We previously observed that in response to stress, the compensatory hypertrophy, protein synthesis, and UNA synthesis are reduced in old compared to young adult hearts. This decreased myocardial reserve in old hearts is associated with an altered program of gene expression. We observed that the basal binding activity to the c-fos serum response element (SRE) in the heart was increased with age, and that serum response factor (SRF), the major SRE binding protein, was also slightly increased in old compared with young adult hearts. Inasmuch as SRF is a key transcription factor in many muscle genes, it is plausible that SRF contributes to the altered expression of these genes. In a genetically modified mouse that was generated with cardiac-specific, moderate overexpression of the wild type SRF gene, there was significant cardiomyocyte hypertrophy, cardiomyopathy and early mortality. The SRF null is embryonically lethal. A dominant negative, mutant SRF transgenic mouse was generated in which the mutations are in the DNA binding domain, thereby severely compromising the mutant SRF's ability to bind to the c-fos SRE; these newborn dominant negative transgenic mice had dilated hearts with abnormally small cardiomyocytes, poor postnatal growth and development, and all died within 12 days after birth. These findings suggest that SRF is essential for cardiac development, growth and maintenance, but that a moderate increase or decrease in cardiac SRF activity can have potentially disastrous consequences in the animal. We sought to determine the effect of mild changes in SRF activity on the heart, and found that in a transgenic mouse with mildly increased SRF activity, there were mild cardiac changes in young adulthood which appeared to be similar to those usually observed in old age. These findings are compatible with the intriguing notion that a transcription factor such as SRF may be involved in mediating, in part, the process of myocardial aging. However, a link between the activity of any gene and aging in the heart has not been previously established. We therefore propose to conduct a detailed investigation of this novel concept, which holds significant potential for the future development of new targets of therapy. The central theme of our proposal is that alterations in a single transcription factor such as SRF may underlie, in part, the aging changes that are commonly observed in the heart. We propose to test this hypothesis and to elucidate the mechanism(s) underlying the aging process of the heart. Our specific aims are: l) To test the hypothesis that the process of cardiac aging might be partly attributable to altered transcription regulation of genes such as the serum response factor (SRF); 2) To test the hypothesis that a mildly reduced level of SRF in the old heart would be associated with delayed cardiac aging; 3) To test the hypothesis that SRF might mediate, in part, aspects of altered calcium handling that has been observed during normal adult cardiac aging.

描述（由申请人提供）：本修订后的申请寻求支持以研究心脏衰老的基本机制。 我们之前观察到，与年轻人相比，老年人心脏在应对压力时，代偿性肥大、蛋白质合成和 UNA 合成减少。老年心脏心肌储备的减少与基因表达程序的改变有关。我们观察到，心脏中c-fos血清反应元件（SRE）的基础结合活性随着年龄的增长而增加，并且与年轻人相比，老年人的主要SRE结合蛋白血清反应因子（SRF）也略有增加成人的心。由于 SRF 是许多肌肉基因中的关键转录因子，因此 SRF 可能会导致这些基因表达的改变。在一只心脏特异性、中度过度表达野生型 SRF 基因的转基因小鼠中，出现了明显的心肌细胞肥大、心肌病和早期死亡。 SRF null 是胚胎致死的。产生了显性失活突变 SRF 转基因小鼠，其中突变位于 DNA 结合域中，从而严重损害了突变 SRF 与 c-fos SRE 结合的能力；这些新生的显性失活转基因小鼠心脏扩张，心肌细胞异常小，出生后生长发育不良，全部在出生后12天内死亡。这些发现表明，SRF 对于心脏发育、生长和维持至关重要，但心脏 SRF 活性的适度增加或减少可能会给动物带来潜在的灾难性后果。我们试图确定 SRF 活性的轻微变化对心脏的影响，并发现在 SRF 活性轻度增加的转基因小鼠中，在青年期出现轻微的心脏变化，这似乎与通常在老年时观察到的情况相似。这些发现与一个有趣的观点相一致，即 SRF 等转录因子可能部分参与介导心肌衰老过程。然而，之前尚未确定任何基因的活性与心脏衰老之间的联系。因此，我们建议对这一新概念进行详细研究，该概念对于未来开发新的治疗靶点具有巨大潜力。我们提议的中心主题是，单一转录因子（例如 SRF）的改变可能部分是心脏中常见的衰老变化的基础。我们建议检验这一假设并阐明心脏衰老过程的潜在机制。我们的具体目标是： l) 检验心脏衰老过程可能部分归因于血清反应因子 (SRF) 等基因转录调控改变的假设； 2) 检验老年心脏中 SRF 水平轻度降低与心脏衰老延迟相关的假设； 3) 检验 SRF 可能部分介导在正常成人心脏衰老过程中观察到的钙处理改变的假设。