EFFECTS OF AGING ON ACUTE PHASE RESPONSE REGULATION

老化对急性期反应调节的影响

• 批准号: 6098418
• 负责人: JOHN NMN PAPACONSTANTINOU
• 金额: $ 32.43万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098418
• 关键词: DNA damage; acute phase protein; aging; alpha 1 acid glycoprotein; animal old age; biological signal transduction; caloric dietary content; cell line; dietary restriction; enhancer binding protein; gene expression; gene induction /repression; glucocorticoids; hormone regulation /control mechanism; juvenile animal; laboratory mouse; lipopolysaccharides; liver cells; liver metabolism; mitochondrial DNA; nutrition related tag; oxidative stress; protein biosynthesis; protein isoforms; translation factor

Age-related changes in the regulation of stress reponse genes are due to altered structure and function of their trans-acting regulators. Our long-range goal is to identify the mechanisms for the age-relted effects on responses to stress factors. We propose that cytokines and reactive oxygen species (ROS), shown to increase in aging, affect the activity of pathways tranducing these mediators' singals, so that aging tissues exhibit characteristics of chronic stress. Our data suggest that the synthesis of C/EBPalpha and C/EBPbeta isoforms is regulated by lipopolysaccharide (LPS); that this involves alternative translational initiation(ATI) at specific in-frame AUG codons withinthe same mRNA; and that ATI characteristic of an inflammatory response in young livers occurs constitutively in aged animals. We propose that ATI occurs via a leaky ribosomal scanning (LRS) mechanism that is linked to specific signal transduction pathways. Specific aim 1 will determine whether the regulation of C/EBP isoform synthesis involves ATI of their mRNAs in young livers and whether ATI is altered in the aged liver. Specific Aim 2 will test whether ATI is constitutive level of activity. Specific Aim 3 demonstrate a linkage of C/EBP isoform synthesis and activation to oxidative stress. We propose that generators of ROS, such as DNA-damaging agents, may trigger the signal pathways that regulate ATI. The role of C/EBP in AP- endonuclease (APE) induction by HOC1, in cellular adaptation to DNA-damaging agents, and APE's inducibility by LPS in aging will be examined. Collaborative experiments to study the effects of mitochondrial DNA-damaged agents, on the regulation of C/EBP isoform synthesis are based on the hypothesis that age-associated increases in ROS may, in part, be due to radicals produced by mitochondrial DNA damage;. We will determine whether p21 (Cip1) is a stress response gene whose expression and regulation involved interaction of C/EBPs with its promoter binding sites. Specific Aim 4 will test the hypothesis that caloric restriction affects regulation of the biological process involving responses to ROS. The data gained by this project lay the foundation for future studies on tissue specific responses to stress, in vivo, and their susceptibility to age-related diseases.

应激反应基因调节中与应激相关的变化是由于 改变了它们的反式调节器的结构和功能。 我们 长期目标是确定年龄相关效应的机制 对压力因素的反应 我们认为，细胞因子和反应性 氧物种（ROS），显示在老化中增加，影响 传导这些介质信号的途径， 表现出慢性压力的特征。 我们的数据表明， C/EBP α和C/EBP β同种型的合成受 脂多糖（LPS）;这涉及替代翻译 起始（ATI）在特定的框内AUG密码子相同 mRNA;和ATI特征性炎症反应， 年轻的肝脏在年老的动物中组成性地出现。 我们建议 ATI通过泄漏核糖体扫描（LRS）机制发生， 与特定的信号转导途径有关。 具体目标1将 确定C/EBP亚型合成的调节是否涉及 ATI的mRNA在年轻的肝脏和ATI是否改变， 老年肝脏 具体目标2将测试ATI是否是 活动 特异性目的3证明C/EBP同种型的连接 合成和活化以抗氧化应激。 我们建议 ROS的产生者，如DNA损伤剂，可能会触发 调节ATI的信号通路。 C/EBP在AP中的作用 在细胞适应中，HOC 1的核酸内切酶（APE）诱导， DNA损伤剂和衰老中LPS诱导的APE将是 考察 合作实验，以研究 线粒体DNA损伤剂，对C/EBP的调节 同种型合成是基于这样的假设，即年龄相关的 ROS的增加可能部分是由于 线粒体DNA损伤; 我们将确定p21（Cip 1） 是一种应激反应基因，其表达和调节涉及 C/EBP与其启动子结合位点的相互作用。 具体目标4 将测试这一假设，即热量限制影响调节 涉及对ROS的反应的生物学过程。 通过以下方式获得的数据 本研究为进一步研究组织特异性 应激反应，在体内，和他们的易感性，年龄相关的 疾病