Targeted membrane integrity in cardiac ischemia and reperfusion

摘要 这项建议的健康相关性是突出的，因为我们关注的是临床上意义重大的 心肌缺血/再灌注损伤(I/R)，这是由于我们对潜在机制的实验强调 以及潜在的治疗方法。心肌I/R损伤每年导致数百万人死亡，严重的 心肌细胞功能障碍和心肌细胞死亡，目前还没有治愈或高度有效的治疗方法。这 该提案具有健全的科学前提和大量的初步数据，表明 心肌膜稳定化在保存I/R心肌组织活性和功能方面具有重要作用。 指导这一建议的科学前提是在I/R中保护心肌细胞膜的完整性 在I/R中维持存活的心肌组织所需的，这对长期成功是必不可少的 结果。我们专注于合成的共聚物作为细胞外源性心肌细胞膜稳定剂。 共聚物基的膜稳定剂是相互作用的两亲性长链大分子共聚物 在应激状态下保护和保护心肌肌膜。指导性假设是合成的共聚物 直接与受损的心肌肌膜对接，以实现稳定。目标1专注于最新情况- ART共聚物-膜界面结构-功能研究。在补语中，Aim 2调查细胞 外源性合成肌膜稳定剂及其与细胞内源性的互补机制 心肌细胞膜的稳定和修复途径以保存存活的心脏组织并增强 在体I/R后关键恢复期的心脏功能。为了推进这些目标，我们利用 一群高度协作的杰出研究人员，他们拥有分子和整合方面的专业知识 生理学、生物化学、化学工程学和临床心脏病学。我们独特的团队是高度互动的 而且相互依赖。共同努力，我们处于推动I/R机制和 实验治疗学。由于获得了机械洞察力，撞击潜力是突出的 最终将指导用于I/R患者的膜稳定剂的治疗发展。

Abstract The health relevance of this proposal is outstanding due to our focus on the clinically significant problem of myocardial ischemia/reperfusion injury (I/R), and due to our experimental emphasis on underlying mechanisms and potential therapies. Myocardial I/R injury causes millions of human deaths per year resulting from severe cardiac myocyte dysfunction and myocyte death, for which there is no cure or highly effective treatment. This proposal features a sound scientific premise and substantial preliminary data indicating the critical role that cardiac muscle membrane stabilization has in preserving cardiac tissue viability and performance in I/R. The scientific premise guiding this proposal is that protecting cardiac muscle cell membrane integrity in I/R is required to maintain viable myocardial tissue in I/R, and that this is essential for long-term successful outcomes. We focus on synthetic copolymers as cell extrinsic cardiac muscle membrane stabilizers. Copolymer-based membrane stabilizers are amphiphilic long-chain macromolecular copolymers that interact with and protect the cardiac sarcolemma during stress. The guiding hypothesis is that synthetic copolymers interface directly with the damaged cardiac sarcolemma to confer stabilization. Aim 1 focuses on state-of-the- art copolymer-membrane interface structure-function investigations. In complement, Aim 2 investigates cell extrinsic synthetic muscle membrane stabilizers and the mechanism of their complementation with cell intrinsic myocardial cell membrane stabilization and repair pathways to preserve viable cardiac tissue and enhance heart performance during the critical recovery phase following I/R in vivo. To advance these Aims, we leverage an outstanding group of highly collaborative investigators spanning expertise in molecular and integrative physiology, biochemistry, chemical engineering, and clinical cardiology. Our unique group is highly interactive and interdependent. Together, we are ideally positioned to propel discovery in I/R mechanisms and experimental therapeutics. Impact potential is outstanding by virtue of the mechanistic insights obtained that will ultimately guide the therapeutic development of membrane stabilizers for I/R patients.