REGULATION OF CARDIAC CONTRACTILITY BY DIACYLGLYCEROL

二酰甘油对心脏收缩的调节

• 批准号: 6479450
• 负责人: JEFFREY W WALKER
• 金额: $ 19.96万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2002-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6479450
• 关键词: biological signal transduction; calcium flux; cardiac myocytes; diacylglycerols; enzyme activity; gene targeting; genetically modified animals; heart contraction; heart pharmacology; laboratory mouse; laboratory rat; microfilaments; muscle relaxation; myocardium; myosin light chain kinase; phosphatidylinositols; protein kinase A; protein kinase C; troponin; unsaturated fatty acids

Abstract. The broad, long-term objectives of the proposed research are to elucidate mechanisms underlying the regulation of myocardial contraction by diacylglycerol and protein kinase C. Many extracellular chemical signals such as hormones, neurotransmitters, cytokines, growth factors, mechanical stress and oxygen stress may regulate cardiac contractility by mobilizing lipid second messengers including diacylglycerol and cis- unsaturated fatty acids. There are at least four enzyme systems, PLA2, PLC-beta, PLC-gamma and PLD involved in generating these lipid messengers giving rise to a potentially information-rich signal encoded in lipid species generating these lipid messengers giving rise to a potentially information-rich signal encoded in lipid species, timing and location in a systematic way in order to establish the influence of these parameters on contractile regulation. cis-Unsaturated fatty acids and Ca will be investigated as putative co-messengers with diacylglycerol that may selectively activate protein kinase C isoforms alpha, epsilon or delta. The mechanisms of protein kinase C anchoring to sites on the transverse tubules and to sites on the myofilament will be examined and their respective roles in regulating systolic Ca levels and myofilament Ca sensitivity will be established. Whether protein kinase C mediated phosphorylation of cardiac troponin I is a major mechanism underlying positive or negative inotropic responses in ventricular myocytes will also be established. The goal is to use a combination of modern and innovative methodologies in cell biophysics, imaging and molecular biology to provide unambiguous answers to fundamental questions about diacylglycerol signaling in the heart. This research will further our understanding of basic mechanisms by which lipid messengers alter cardiac physiology, and mechanisms of protein kinase C regulation of cardiac troponin I function, so that defects in these pathways in various diseased states can be identified and corrected. The proposed research will be highly interactive with other subprojects and will rely to a significant extent on the expertise of other investigators in the Program. Overall, this research addresses a major theme of the Program involving elucidation of signal transduction mechanisms evoked by membrane receptor antagonists in myocardium.

抽象的。这项研究的长期目标是阐明甘油二酯和蛋白激酶C调节心肌收缩的机制。许多细胞外化学信号如激素、神经递质、细胞因子、生长因子、机械应激和氧应激可通过动员脂质第二信使（包括甘油二酯和顺式不饱和脂肪酸）来调节心脏收缩力。至少有四种酶系统，PLA 2、PLC-β、PLC-γ和PLD参与产生这些脂质信使，产生在脂质物质中编码的潜在信息丰富的信号，以系统的方式产生这些脂质信使，产生在脂质物质中编码的潜在信息丰富的信号，定时和定位，以建立这些参数对收缩调节的影响。将研究顺式不饱和脂肪酸和Ca作为可能选择性激活蛋白激酶C亚型α、β或δ的二酰基甘油的推定共同信使。将检查蛋白激酶C锚定到横小管上的位点和肌丝上的位点的机制，并建立它们各自在调节收缩期Ca水平和肌丝Ca敏感性中的作用。还将确定蛋白激酶C介导的心肌肌钙蛋白I磷酸化是否是心室肌细胞正性或负性变力性反应的主要机制。我们的目标是使用细胞生物物理学，成像和分子生物学中的现代和创新方法的组合，为心脏中甘油二酯信号传导的基本问题提供明确的答案。这项研究将进一步了解脂质信使改变心脏生理学的基本机制，以及蛋白激酶C调节心肌肌钙蛋白I功能的机制，从而可以识别和纠正各种疾病状态下这些途径的缺陷。拟议的研究将与其他子项目高度互动，并将在很大程度上依赖于该计划中其他研究人员的专业知识。总体而言，这项研究解决了该计划的一个主要主题，涉及心肌膜受体拮抗剂引起的信号转导机制的阐明。