Mitoprotective and antioxidant peptides for DM treatment

描述（由申请人提供）： 该提案旨在确定减少线粒体活性氧（ROS）产生并减少氧化应激诱导的组织损伤的靶向药物候选物。我们最近发现了一个家族的小细胞可渗透的芳香族阳离子肽（SS肽），选择性地针对线粒体，并具有抗氧化性能。迄今为止的研究表明，这些肽在保护神经元细胞系免受氧化应激诱导的凋亡和坏死方面非常有效，并且证明了它们在离体和体内均具有保护免受缺血-再灌注损伤的能力。初步研究进一步表明，这些肽可以通过不涉及清除ROS的机制阻止线粒体通透性转换。最令人惊讶的是，这些肽具有优异的药代动力学特性，并且迄今为止在动物研究中未显示出任何毒性。我们现在正在寻求短期的支持，以探索这些新的线粒体保护和抗氧化肽在减少高血糖症的有害影响的潜力。本研究将着重探讨高血糖和活性氧对胰岛细胞和内皮细胞的影响。我们的具体目标是：1。目的：1.研究SS-31对高糖诱导的内皮细胞和胰岛细胞死亡的影响。测定SS-31降低高糖暴露的内皮细胞和小鼠胰岛氧化应激的能力; 3.确定SS-31的作用部位和机制。我们建议证明SS-31：1）易于穿透内皮细胞和小鼠胰岛; 2）定位并浓缩在线粒体中; 3）减少高糖诱导的细胞内ROS产生; 4）保护暴露于高糖的细胞中的线粒体电位; 5）防止暴露于高糖的细胞中线粒体钙超载。这些探索性研究的结果将指导我们开展临床前动物研究，以评价SS- 31治疗糖尿病和胰岛移植的治疗潜力。

DESCRIPTION (provided by applicant): This proposal seeks to identify mitochondrial-targeted drug candidates that decrease mitochondrial reactive oxygen species (ROS) production and reduce oxidative stress-induced tissue damage. We recently discovered a family of small cell-permeable aromatic-cationic peptides (SS peptides) that selectively targets mitochondria and possess antioxidant properties. Studies to date have shown that these peptides are very potent in protecting against oxidative stress-induced apoptosis and necrosis in neuronal cell lines, and demonstrated their ability to protect against ischemia-reperfusion injury both ex vivo and in vivo. Preliminary studies further suggest that these peptides can prevent mitochondrial permeability transition via a mechanism that does not involve scavenging of ROS. Most encouragingly, these peptides have excellent pharmacokinetic profiles and have not demonstrated any toxicity to date in animal studies. We are now seeking short-term support to explore the potential of these novel mitoprotective and antioxidant peptides in reducing the deleterious effects of hyperglycemia. The proposed studies will focus on the effects of hyperglycemia and ROS on pancreatic islet cells and endothelial cells. Our Specific Aims are: 1. To investigate the ability of SS-31 to reduce cell death in endothelial cells and mouse pancreatic islets induced by high glucose; 2. To determine the ability of SS-31 to reduce oxidative stress in endothelial cells and mouse pancreatic islets exposed to high glucose; 3. To determine the site and mechanism(s) of action of SS-31. We propose to demonstrate that SS-31: 1) readily penetrates endothelial cells and mouse pancreatic islets; 2) localizes and concentrates in mitochondria; 3) reduces intracellular ROS production induced by high glucose; 4) protects mitochondrial potential in cells exposed to high glucose; and 5) prevents mitochondrial calcium overload in cells exposed to high glucose. The results from these exploratory studies will guide us to the development of preclinical animal studies for evaluating the therapeutic potential of SS- 31 in the treatment of diabetes and for pancreatic islet transplantation.