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.