Cytoplasmic Glycosylation and Hypovolemic Stress

细胞质糖基化和低血容量应激

• 批准号: 6843142
• 负责人: Richard Banfield Marchase
• 金额: $ 36.25万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6843142
• 关键词: N acetylglucosamine; calcium flux; cardiac myocytes; cardiovascular disorder chemotherapy; cytoplasm; cytoprotection; disease /disorder model; glucosamine; glycoprotein biosynthesis; glycosylation; heat shock proteins; hexosamines; hexosyltransferase; hypovolemia; laboratory rat; nonhuman therapy evaluation; swine

DESCRIPTION (provided by applicant): The hypothesis to be tested here is that interventions following trauma that increase the glycosylation of nucleocytoplasmic proteins in cardiomyocytes decrease the cellular damage that would otherwise contribute to hypovolemic circulatory collapse. Our preliminary data demonstrate that in a rat model of hypovolemic stress, the infusion of glucosamine leads to a striking improvement in post-trauma function. We also demonstrate that glucosamine is protective in isolated heart models of ischemia/reperfusion and calcium overload. We propose that this protection results from an amplification of a natural, stress-activated, pro-survival pathway triggered by increased flux through the hexosamine biosynthesis pathway (HBP). The capacity to transduce an increase in the HBP's primary product, UDP-GIcNAc, into complex cellular responses comes about because O-GIcNAc transferase (OGT) is activated and recognizes distinct proteins as levels of UDP-GIcNAc increase. The identification of heat shock protein (HSP)-70 as an HBP-induced protein substrate for the OGT and the finding that HSP's associate with other proteins in part based on their ability to bind O-GIcNAc position this pathway at the center of a primary cellular response to stress. In support of this central role for O-GIcNAc in cellular protection, it is now clear that various stresses lead to increases in levels of both UDP-GIcNAc and protein-associated O-GIcNAc. We suggest that interventions that amplify and/or accelerate increases in O-GIcNAc greatly decrease the damage resulting from stress, particularly hypovolemic stress. Our Specific Aims are: to optimize recovery in the rat model of hypovolemic stress through interventions that increase UDP-GIcNAc and to test the efficacy of these interventions in swine; to test the hypothesis that the mechanism by which increased UDP-GIcNAc leads to its ameliorating effects is because of an increase in O-GIcNAc on nuclear and cytoplasmic proteins; to document and identify the nucleocytoplasmic proteins in the heart that are preferentially derivatized with O-GIcNAc when protection is optimized in the hypovolemic rat model; to investigate the decrease in calcium influx seen with increased UDP-GIcNAc in mediating improved recoveries.

描述（由申请人提供）： 这里要检验的假设是，在心肌细胞中增加核质蛋白糖基化的创伤后的干预措施减少了细胞损伤，否则会导致低血液循环崩溃。我们的初步数据表明，在低血容量应激的大鼠模型中，输注葡萄糖胺会导致创伤后功能的显着改善。 我们还证明，葡萄糖胺在缺血/再灌注和钙超负荷的孤立心脏模型中具有保护性。我们提出，这种保护是由天然，应激激活，促生存的途径的放大而引起的，该途径是由通过己糖胺生物合成途径（HBP）增加的通量触发的。由于O-GICNAC转移酶（OGT）激活了HBP的主要产物UDP-GICNAC，将HBP的主要产物UDP-GICNAC引起的能力增加了，并将其识别为UDP-GICNAC的水平增加。热激蛋白（HSP）-70鉴定为HBP诱导的OGT蛋白底物，以及HSP与其他蛋白质相关的发现，部分基于它们结合O-GICNAC位置的能力 主要细胞反应应力反应的途径。支持这个中心角色 O-GICNAC在细胞保护方面，现在很明显，各种应力会导致UDP-GICNAC和与蛋白质相关的O-GICNAC的水平增加。我们建议，放大和/或加速O-GICNAC的干预措施大大减少了由于压力，尤其是低血症性压力而造成的损害。我们的具体目的是：通过增加UDP-GICNAC的干预措施来优化大鼠低血容量应力的恢复，并测试这些干预措施在猪中的功效；为了检验增加UDP-GICNAC导致其改善作用的机制的假设是因为O-GICNAC对核和细胞质蛋白的增加。记录和识别心脏中核细胞质蛋白在低血容量大鼠模型中优化时优先用O-GICNAC衍生的核细胞蛋白；为了研究随着UDP-GICNAC的增加，在介导改进的回收率时，观察到的钙流入减少。