AGING AND OXIDATION IN SKELETAL AND CARDIAC MUSCLE

骨骼肌和心肌的老化和氧化

基本信息

  • 批准号:
    6201024
  • 负责人:
  • 金额:
    $ 13.26万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    1999
  • 资助国家:
    美国
  • 起止时间:
    1999-08-01 至 2001-04-14
  • 项目状态:
    已结题

项目摘要

Our long-term goal is to understand the role of protein and lipid oxidation in age-related modifications of calcium regulation in the heart. Our focus will be on the sarcoplasmic reticulum (SR) Ca-ATPase, an active transport protein that is central to the maintenance of low resting levels of intracellular calcium and normal myocardial relaxation. Effects of oxidation, aging, and susceptibility to oxidative stress will be examined for the protein and lipid components of SR membranes. Much of this work will rely on comparison with results from similar studies with skeletal SR, where the skeletal Ca-ATPase isoform is more abundant and the membrane composition is simpler. Our three specific aims are: FIRST, to identify oxidative modifications of the Ca-ATPase, its regulatory protein, phospholamban, and SR lipids, initiated by exposure of isolated SR vesicles to reactive oxygen species. We will emphasize reactive oxygen species whose chemistry is simple and allows quantification. These free radicals will be targeted to either the lipid bilayer or to the aqueous medium, in order to specifically oxidize membrane-spanning or soluble peptides. In this way we seek insight into mechanisms of oxidative damage to cellular proteins. The relationship between reactive oxygen species and function is not available from biologically aged samples where a large number of reactions, coupled with the presence of cellular repair mechanisms complicate our understanding of processes leading to protein damage. SECOND, we will define the role of the cellular environment in modifying the susceptibility of SR membranes to oxidative conditions. This approach, utilizing primary cultures of myocytes, will provide an opportunity to examine the effect of oxidative conditions on protein and lipid turnover. Using the knowledge gained from these model systems, we will (THIRDLY), identify age-related oxidative modifications, and their associated structural and functional consequences. Work with both model and biologically aged systems will emphasize quantitative identification of the products of free radical-mediated modifications of proteins and lipids. The combined use of fluorescence and spin-label electron paramagnetic resonance spectroscopies will provide information regarding protein conformation and bilayer dynamics. An increased understanding of age-related molecular defects of calcium regulation in cardiac muscle is relevant to human health, since oxidation of biomolecules is thought to play a major role in aging and myocardial infarction. This understanding is necessary for the design of effective therapies for delaying the onset and progress of decreased myocardial function and susceptibility to oxidative stress.
我们的长期目标是了解蛋白质和脂肪的作用 心脏钙调节的年龄相关修饰中的氧化作用。 我们的重点将放在肌浆网(SR)的Ca-ATPase上,它是一种活跃的 对维持低静息水平至关重要的转运蛋白 细胞内钙和正常的心肌松弛。的效果 本课程将研究氧化、老化和对氧化应激的敏感性。 用于SR膜的蛋白质和脂肪成分。这些工作有很大一部分 将依赖于与骨骼的类似研究结果的比较 SR,骨骼Ca-ATPase同工酶较丰富的地方,膜 构图更简单。我们的三个具体目标是:第一,确定 Ca-ATPase的氧化修饰,它的调节蛋白, 由分离的SR暴露引发的磷蛋白和SR脂 从囊泡到活性氧物种。我们将强调活性氧 化学性质简单且可定量的物种。这些是免费的 自由基将被靶向脂双层或水分子。 介质,以特定的氧化膜-跨膜或可溶 多肽。通过这种方式,我们寻求对氧化损伤机制的洞察。 到细胞蛋白质。活性氧自由基之间的关系 和功能不能从生物老化的样品中获得,在那里 反应的数量,加上细胞修复的存在 机制使我们对蛋白质形成过程的理解复杂化 损坏。第二,我们将定义蜂窝环境在 改善SR膜对氧化条件的敏感性。 这种方法,利用原代培养的心肌细胞,将提供 研究氧化条件对蛋白质和蛋白质影响的机会 脂类周转率。利用从这些模型系统中获得的知识,我们 Will(第三),确定与年龄相关的氧化修饰及其 相关的结构和功能后果。可同时使用两种型号 而生物老化系统将强调定量识别 自由基介导的蛋白质修饰产物和 脂类。荧光和自旋标记电子的联合应用 顺磁共振波谱学将提供关于 蛋白质构象和双层动力学。加深对……的理解 与年龄相关的心肌钙调节分子缺陷是 与人类健康有关,因为生物分子的氧化被认为是 在衰老和心肌梗死中起主要作用。这一理解 对于设计有效的延缓发病的治疗方法是必要的 心肌功能和易感性降低的研究进展 氧化应激。

项目成果

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Diana Jean Bigelow其他文献

Diana Jean Bigelow的其他文献

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{{ truncateString('Diana Jean Bigelow', 18)}}的其他基金

3-NITROTYROSINE IN AGING OF SKELETAL MUSCLE AND HEART
3-硝基酪氨酸在骨骼肌和心脏老化中的作用
  • 批准号:
    6594402
  • 财政年份:
    2000
  • 资助金额:
    $ 13.26万
  • 项目类别:
3-NITROTYROSINE IN AGING OF SKELETAL MUSCLE AND HEART
3-硝基酪氨酸在骨骼肌和心脏老化中的作用
  • 批准号:
    6509742
  • 财政年份:
    2000
  • 资助金额:
    $ 13.26万
  • 项目类别:
3-NITROTYROSINE IN AGING OF SKELETAL MUSCLE AND HEART
3-硝基酪氨酸在骨骼肌和心脏老化中的作用
  • 批准号:
    6372485
  • 财政年份:
    2000
  • 资助金额:
    $ 13.26万
  • 项目类别:
3-NITROTYROSINE IN AGING OF SKELETAL MUSCLE AND HEART
3-硝基酪氨酸在骨骼肌和心脏老化中的作用
  • 批准号:
    6094056
  • 财政年份:
    2000
  • 资助金额:
    $ 13.26万
  • 项目类别:
AGING AND OXIDATION IN SKELETAL AND CARDIAC MUSCLE
骨骼肌和心肌的老化和氧化
  • 批准号:
    6098640
  • 财政年份:
    1998
  • 资助金额:
    $ 13.26万
  • 项目类别:
AGING AND OXIDATION IN SKELETAL AND CARDIAC MUSCLE
骨骼肌和心肌的老化和氧化
  • 批准号:
    6234545
  • 财政年份:
    1997
  • 资助金额:
    $ 13.26万
  • 项目类别:
AGING AND OXIDATION IN SKELETAL AND CARDIAC MUSCLE
骨骼肌和心肌的老化和氧化
  • 批准号:
    6029721
  • 财政年份:
    1996
  • 资助金额:
    $ 13.26万
  • 项目类别:
AGING AND OXIDATION IN SKELETAL AND CARDIAC MUSCLE
骨骼肌和心肌的老化和氧化
  • 批准号:
    2732479
  • 财政年份:
    1996
  • 资助金额:
    $ 13.26万
  • 项目类别:
AGING AND OXIDATION IN SKELETAL AND CARDIAC MUSCLE
骨骼肌和心肌的老化和氧化
  • 批准号:
    6168632
  • 财政年份:
    1996
  • 资助金额:
    $ 13.26万
  • 项目类别:
AGING AND OXIDATION IN SKELETAL AND CARDIAC MUSCLE
骨骼肌和心肌的老化和氧化
  • 批准号:
    2442198
  • 财政年份:
    1996
  • 资助金额:
    $ 13.26万
  • 项目类别:

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醛固酮相关高血压与钙代谢之间的内分泌串扰
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