Cytoplasmic Glycosylation and Hypovolemic Stress

细胞质糖基化和低血容量应激

基本信息

项目摘要

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,创伤后增加心肌细胞核质蛋白糖基化的干预措施减少了细胞损伤,否则会导致低血容量性循环衰竭。我们的初步数据表明,在低血容量应激的大鼠模型中,葡萄糖胺的输注导致创伤后功能的显著改善。 我们还表明,葡萄糖胺是保护在离体心脏模型的缺血/再灌注和钙超载。我们提出,这种保护的结果从一个自然的,应激激活的,促生存途径的放大触发增加通量通过己糖胺生物合成途径(HBP)。将HBP的主要产物UDP-GlcNAc的增加转化为复杂的细胞反应的能力是因为O-GlcNAc转移酶(OGT)被激活并随着UDP-GlcNAc水平的增加识别不同的蛋白质。热休克蛋白(HSP)-70作为OGT的HBP诱导蛋白底物的鉴定以及HSP与其他蛋白质结合的发现部分基于它们结合O-GlcNAc位置的能力。 在一个主要的细胞应激反应的中心途径。为了支持这一中心作用, O-GlcNAc在细胞保护中的作用,现在清楚的是,各种应激导致UDP-GlcNAc和蛋白相关O-GlcNAc水平的增加。我们认为,放大和/或加速O-GIcNAc增加的干预措施大大减少了压力,特别是低血容量压力造成的损害。我们的具体目标是:通过增加UDP-GlcNAc的干预措施优化低血容量应激大鼠模型的恢复,并在猪中测试这些干预措施的有效性;测试UDP-GlcNAc增加导致其改善作用的机制是由于细胞核和细胞质蛋白上O-GlcNAc增加的假设;记录和鉴定在低血容量大鼠模型中优化保护时,心脏中优先用O-GlcNAc衍生的核质蛋白;研究UDP-GlcNAc增加介导恢复改善时钙内流的减少。

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Increased O-linked beta-N-acetylglucosamine levels on proteins improves survival, reduces inflammation and organ damage 24 hours after trauma-hemorrhage in rats.
  • DOI:
    10.1097/ccm.0b013e3181cb10b3
  • 发表时间:
    2010-02
  • 期刊:
  • 影响因子:
    8.8
  • 作者:
    Nöt LG;Brocks CA;Vámhidy L;Marchase RB;Chatham JC
  • 通讯作者:
    Chatham JC
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Richard Banfield Marchase其他文献

Richard Banfield Marchase的其他文献

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{{ truncateString('Richard Banfield Marchase', 18)}}的其他基金

Construction/SEBLAB/Regional Biocontainment Laboratory
建筑/SEBLAB/区域生物防护实验室
  • 批准号:
    7212514
  • 财政年份:
    2006
  • 资助金额:
    $ 34.37万
  • 项目类别:
Cytoplasmic Glycosylation and Hypovolemic Stress
细胞质糖基化和低血容量应激
  • 批准号:
    7006683
  • 财政年份:
    2004
  • 资助金额:
    $ 34.37万
  • 项目类别:
EXTRAMURAL RESEARCH FACILITIES IMPROVEMENT: NEUROSCIENCE
校外研究设施的改进:神经科学
  • 批准号:
    6972988
  • 财政年份:
    2004
  • 资助金额:
    $ 34.37万
  • 项目类别:
EXTRAMURAL RESEARCH FACILITIES IMPROVEMENT: PHYSIOLOGY
校外研究设施的改进:生理学
  • 批准号:
    6972991
  • 财政年份:
    2004
  • 资助金额:
    $ 34.37万
  • 项目类别:
EXTRAMURAL RESEARCH FACILITIES IMPROVEMENT: IMMUNOLOGY
校外研究设施的改进:免疫学
  • 批准号:
    6972989
  • 财政年份:
    2004
  • 资助金额:
    $ 34.37万
  • 项目类别:
EXTRAMURAL RESEARCH FACILITIES IMPROVEMENT: AIDS
校外研究设施的改进:艾滋病
  • 批准号:
    6972987
  • 财政年份:
    2004
  • 资助金额:
    $ 34.37万
  • 项目类别:
EXTRAMURAL RESEARCH FACILITIES IMPROVEMENT
校外研究设施的改善
  • 批准号:
    6829193
  • 财政年份:
    2004
  • 资助金额:
    $ 34.37万
  • 项目类别:
EXTRAMURAL RESEARCH FACILITIES IMPROVEMENT: ENVIRONMENTAL HEALTH
校外研究设施改进:​​环境健康
  • 批准号:
    6972990
  • 财政年份:
    2004
  • 资助金额:
    $ 34.37万
  • 项目类别:
Cytoplasmic Glycosylation and Hypovolemic Stress
细胞质糖基化和低血容量应激
  • 批准号:
    6843142
  • 财政年份:
    2004
  • 资助金额:
    $ 34.37万
  • 项目类别:
Cytoplasmic Glycosylation and Hypovolemic Stress
细胞质糖基化和低血容量应激
  • 批准号:
    6754162
  • 财政年份:
    2004
  • 资助金额:
    $ 34.37万
  • 项目类别:

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