OXIDATION AND AGING IN CARDIAC AND SKELETAL MUSCLE

我们的长期目标是了解蛋白质（和脂质）的作用 心肌细胞钙调节的年龄相关性改变中的氧化作用 和骨骼肌。 我们的重点涉及两种对钙起核心作用的蛋白质 肌肉中的调节：（a）内在膜蛋白，Ca-ATPase （B）可溶性蛋白钙调素。 具体而言，我们的目标是：（1）启动模型研究，以确定 体外蛋白质修饰结构和功能结果 生理学上相关的自由基物质，其化学性质允许 其量化。 这些自由基将被靶向到 脂质双层或水性介质，以便特异性地氧化 跨膜肽或可溶性肽。 这样我们 寻求获得关于相对角色的机械信息 特异性活性氧对细胞氧化损伤的影响 proteins. 活性氧与功能的关系 在生物老化的系统中， 再加上细胞修复机制的存在， 使我们对导致蛋白质损伤的过程的理解变得复杂。 在 为了理解信息的生理相关性， 从模型系统获得，（2）我们将确定年龄相关的氧化 蛋白质和SR脂质的修饰，以及相关的结构 和功能改变。 (3)最后，我们将启动类似的 研究确定年龄相关的分子缺陷的更高 调节心肌SR的Ca-ATPase。 老化的系统将强调产品的定量识别 自由基介导的蛋白质和脂质的修饰。 的 荧光和自旋标记电子顺磁的组合使用 构象和双层结构。 对年龄的了解越来越多- 心脏和心肌细胞中钙调节的相关分子缺陷 骨骼肌与人体健康有关，因为 生物分子在衰老过程中起着重要作用。 这种理解 这反过来又是设计有效疗法的必要条件 用于延迟肌肉功能下降的发作和进展。

Our long-term goal is to understand the role of protein (and lipid) oxidation in age-related modifications of calcium regulation in cardiac and skeletal muscle. Our focus involves two proteins central to calcium regulation in muscle: (a) the intrinsic membrane protein, the Ca-ATPase of sarcoplasmic reticulum (SR), and (b) the soluble protein, calmodulin. Specifically, we aim to: (1) initiate model studies to identify the structural and functional consequences of in vitro protein modification by physiologically relevant free radical species, whose chemistry allows their quantification. These free radicals will be targeted either to the lipid bilayer or to the aqueous medium, in order to specifically oxidize membrane-spanning or soluble peptides, respectively. In this way, we seek to gain mechanistic information regarding the relative roles specific reactive oxygen species to the oxidative damage of cellular proteins. The relationship between reactive oxygen species and function is not available from biologically aged systems where the large number of reactions, coupled with the presence of cellular repair mechanisms, complicate our understanding of processes leading to protein damage. In order to understand the physiological relevance of the information obtained from model systems, (2) we will identify age-related oxidative modifications of protein and SR lipids, as well as associated structural and functional alterations. (3) Finally, we will initiate similar studies to identify age-related molecular defects of the more highly regulated Ca-ATPase of cardiac SR. 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 conformation and bilayer structure. An increased understanding of age- related molecular defects of calcium regulation in both cardiac and skeletal muscle is relevant to human health, since oxidation of biomolecules is though to play a major role in aging. This understanding in turn, is a necessary requirement for the design of effective therapies for delaying the onset and progress of decreased muscle function.