SIGNAL REGULATION OF CARDIAC CYTOKINE SYNTHESIS AND MECHANICAL FUNCTION

心脏细胞因子合成和机械功能的信号调节

• 批准号: 6584177
• 负责人: JURETA W HORTON
• 金额: $ 19.72万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-01 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6584177
• 关键词: biological signal transduction; burn therapy; burns; calcium flux; heart function; inflammation; interleukin 1; laboratory mouse; laboratory rat; myocardium; nitric oxide synthase; nuclear factor kappa beta; protein biosynthesis; protein kinase; protein localization; sphingosine; tissue /cell culture; tumor necrosis factor alpha

Studies suggest that TNF synthesis by cardiomyocytes may contribute to cardiac dysfunction in a number of insults including septic shock, thermal injury, congestive heart disease. Compartmentalized TNF production within the heart by be significantly higher than is reflected by systemic TNF levels, and locally produced TNF may not be buffered by circulating TNF receptors which would have limited access to intramyocardially produced TNF. The overall objectives of this proposal are to define the signal transduction mechanisms which regulate posture myocardial TNF production and to define the mechanisms by which TNF altars cardiac function. We hypothesize that phosphorylation and degradation of IkappaB and nuclear translocation of NF-kappaB are critical modulators and posture TNF transcriptional events within the myocardium. We further hypothesize that burn-mediated increases in cardiac TNF synthesis induce a cascade of mediators which contribute to remodeling of the cardiomyocyte cytoskeleton, alter myofibrillar binding to Ca2+ and produce cardiac injury. We will examine the global hypothesis that TNF is a proximal mediator of the overall inflammatory response to burn trauma: Five specific aims will be: 1) determine the effects of burn trauma on myocardial TNF mRNA and protein and determine the cellular source and subcellular location of myocardial TNF synthesis; 2) determine the role of NF-kappaB in posture cardiomyocyte TNF synthesis and identify secretagogues triggered by cutaneous burn injury which regulate NF-kappaB/TNF synthesis; 3) determine the intracellular signaling mechanisms which regulate NF-kappaB ACTIVATION/TNF synthesis; 3) determine the intracellular signaling mechanisms which regulate NF-kappaB activation/TNF synthesis in cardiomyocytes; 4) determine if cardiac derived TNF after burn trauma exerts negative inotropic effects via induction of iNOS, expression of IL-1, or production of cardiac sphingosine; and 5) determine if TNF modulates if TNF modulates cardiac function by altering cellular handling of Ca2+, which in turn, promotes gelsolin-mediated myocyte cytoskeletal remodeling. We will focus on identifying the inducer(s) and signal transduction pathways which lead to TNF secretion by cardiomyocytes as well as specific mechanisms by which TNF produces myocardial injury and dysfunction. These studies should allow development of therapeutic strategies that would provide significant cardioprotection not only for victims of burn trauma but also for patient populations in whom impaired cardiac contraction/relaxation contribute to increased mortality.

研究表明，心肌细胞合成TNF可能导致许多损伤的心功能障碍，包括感染性休克、热损伤、充血性心脏病。区隔化的肿瘤坏死因子在心脏内的产生可能明显高于全身肿瘤坏死因子的水平，局部产生的肿瘤坏死因子可能不会被循环的肿瘤坏死因子受体所缓冲，这将限制心肌内产生的肿瘤坏死因子的获取。本提案的总体目标是确定调节姿势心肌TNF产生的信号转导机制，并确定TNF影响心功能的机制。我们假设IkappaB的磷酸化和降解以及NF-kappaB的核易位是心肌内TNF转录事件的关键调节剂和姿态。我们进一步假设，烧伤介导的心脏TNF合成的增加诱导了一系列介质的级联反应，这些介质有助于心肌细胞骨架的重塑，改变肌纤维与Ca2+的结合并产生心脏损伤。我们将研究TNF是烧伤创伤整体炎症反应的近端介质的全球假设：五个具体目标将是：1)确定烧伤创伤对心肌TNF mRNA和蛋白的影响，确定心肌TNF合成的细胞来源和亚细胞位置；2)确定NF-kappaB在体位心肌细胞TNF合成中的作用，确定皮肤烧伤触发的调节NF-kappaB/TNF合成的分泌物；3)确定调节NF-kappaB活化/TNF合成的细胞内信号传导机制；3)确定心肌细胞内调节NF-kappaB活化/TNF合成的细胞内信号机制；4)确定烧伤后心脏源性TNF是否通过诱导iNOS、IL-1表达或产生心脏鞘氨醇产生负性肌力效应；5)确定TNF是否通过改变细胞对Ca2+的处理来调节心功能，进而促进凝胶介导的心肌细胞骨架重塑。我们将专注于识别导致心肌细胞分泌TNF的诱导剂和信号转导途径，以及TNF产生心肌损伤和功能障碍的具体机制。这些研究应该允许制定治疗策略，不仅为烧伤受害者提供重要的心脏保护，也为心脏收缩/舒张受损导致死亡率增加的患者群体提供重要的心脏保护。