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的重大问题， 心肌缺血/再灌注损伤（I/R），由于我们的实验重点是潜在的机制 和潜在的治疗方法心肌I/R损伤每年导致数百万人死亡， 心肌细胞功能障碍和心肌细胞死亡，对此没有治愈或高度有效的治疗。这 该提案具有合理的科学前提和大量的初步数据，表明 在I/R中，心肌膜稳定在保持心脏组织活力和性能方面具有重要意义。的 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， 需要在I/R中维持存活的心肌组织，这对于长期成功的 结果。我们专注于合成共聚物作为细胞外源性心肌膜稳定剂。 基于共聚物的膜稳定剂是两亲性长链大分子共聚物， 在应激过程中保护心肌细胞膜。指导性假设是合成共聚物 直接与受损的心脏肌膜连接以提供稳定性。目标1侧重于国家- 共聚物-膜界面结构-功能研究。作为补充，Aim 2研究细胞 外源性合成肌膜稳定剂及其与细胞内源性互补机制 心肌细胞膜的稳定和修复途径，以保护有活力的心脏组织， 在体内I/R后关键恢复期的心脏性能。为了推进这些目标，我们利用 一组杰出的高度合作的研究人员，他们跨越了分子和整合领域的专业知识， 生理学、生物化学、化学工程和临床心脏病学。我们独特的小组是高度互动的 和相互依赖。总之，我们处于理想的位置，以推动发现I/R机制， 实验治疗学影响潜力是突出的凭借机械的见解， 将最终指导I/R患者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.