Generation and Solution Reactivity of Nitroxyl (HNO)

该研究将涉及硝酰基（HNO）的产生和溶液反应性，该物质最近受到了极大的关注，特别是作为目前心力衰竭治疗的潜在替代品。由于其固有的反应性，HNO必须原位产生，但目前仅存在非常有限数量的适当前体。HNO化学研究的困难在于，目前还没有一种可行的方法来直接检测HNO在溶液或生物相关制剂中的含量。为了解决目前对HNO化学和生物化学、可用的HNO供体分子以及实际有用的HNO直接检测技术的理解不足，拟议的研究将开发（1）新的生理上有用的HNO热前体，（2）适合于纳秒时间分辨红外（TRIR）研究的HNO新的光化学前体，和（3）用于其在水溶液中的检测和研究的新的分析工具。新的HNO供体的开发，结合反应性研究和HNO诱导的蛋白质修饰的评价，不仅将提供对HNO生物活性的基本认识，而且还可能最终导致开发用于治疗心力衰竭的一类新化合物。此外，拟议的研究开发新的热和光化学前体HNO，新的分析工具，其检测，并阐明HNO诱导的PLN修改将提供广泛的培训研究生和本科生。将继续积极鼓励本科生参与研究。

The research will involve the generation and solution reactivity of nitroxyl (HNO), which has recently received significant attention, especially as a potential alternative to current treatments of cardiac failure. Due to its inherent reactivity, HNO must be generated in situ, but only a very limited number of appropriate precursors currently exist. Adding to the difficulty of studying HNO chemistry is that a viable method for its direct detection in solution or biologically relevant preparations is not currently available.To address current deficiencies in the understanding of HNO chemistry and biochemistry, in available HNO donor molecules, and in practically useful direct HNO detection techniques, the proposed research will develop (1) new physiologically useful thermal precursors to HNO, (2) new photochemical precursors to HNO suitable for nanosecond time-resolved infrared (TRIR) investigations, and (3) new analytical tools for its detection and study in aqueous solutions. The development of new HNO donors, combined with reactivity studies and the evaluation of HNO-induced protein modifications, will not only provide fundamental insight into the biological activity of HNO, but may also ultimately lead to the development of a new class of compounds for the treatment of heart failure. In addition, proposed research on the development of new thermal and photochemical precursors to HNO, new analytical tools for its detection, and elucidation of HNO-induced modifications of PLN will afford broad training for graduate students and undergraduates. Undergraduate participation in research will continue to be actively encouraged.