STRUCTURE/FUNCTION OF S-NITROSOHEMOGLOBIN

该项目的长期目标是提高我们对血红蛋白（Hb）依赖no的氧转运功能的理解。在肺中，NO在氧合时与Hb的硫醇结合（R结构），在脱氧时(S)NO组在外周释放（T结构）。因此，Hb的变构控制NO释放参与了外周血流量的调节。然而，对于NO如何影响Hb的功能行为，即其O2结合和变构特性，或NO对肺血管张力或区域通气-灌注关系（V/Q）的影响知之甚少，所有这些都对组织氧合有重要影响。以下假设将得到验证：1)亚硝基化可以以一种有意义的方式影响Hb的协同特性，要么通过增加O2亲和力，要么通过促进O2在周围的释放（即，分别通过结合硫醇或血红素来加强R或T结构）。2) s -亚硝基血红蛋白（SNO-Hb）对肺血管张力和V/Q匹配的影响依赖于PO2。3)对SNO-Hb和亚硝基hb的结构和功能行为的进一步了解可以用于测量人类血液中的这些物种。最终，这些研究将有助于更好地理解NO与蛋白之间的功能调节相互作用、Hb的呼吸功能以及肺血管张力的o2依赖性控制。我们的研究结果也可能对脓毒症、镰状细胞性贫血和新生儿持续性肺动脉高压等疾病状态有影响，也可能对吸入NO等治疗环境有影响，这些治疗环境会改变O2输送和Hb功能。

The long-term goal of this project is to improve our understanding of the NO-dependent O2 transport functions of hemoglobin (Hb). In the lung, NO binds to the thiol of Hb upon oxygenation (R conformation), and the (S)NO group is released in the periphery upon deoxygenation (T structure). Thus, allosterically-controlled NO release from Hb participates in the regulation of peripheral blood flow. However, very little is known of how NO affects the functional behavior of Hb, i.e., its O2 binding and allosteric properties, or what effect NO has on pulmonary vascular tone or regional ventilation-perfusion relationships (V/Q), all of which critically influence tissue oxygenation. The following hypotheses will be tested: 1) That nitrosylation can affect the cooperative properties of Hb in a meaningful way, either by increasing O2 affinity or by facilitating O2 release in the periphery (i.e., by reinforcing the R or T structures through binding thiols or hemes, respectively). 2) That the effects of S-nitrosohemoglobin (SNO-Hb) on pulmonary vascular tone and V/Q matching are dependent on the PO2. 3) That an improved understanding of the structure and the functional behavior of SNO-Hb and nitrosylHb can be used to make measurements of these species in human blood. Ultimately, these studies should lead to a better understanding of the function-regulating interactions between NO and protein, the respiratory functions of Hb, and the O2-dependent control of pulmonary vascular tone. Our results may also have implications in disease states such as sepsis, sickle cell anemia, and persistent pulmonary hypertension of the newborn, and in therapeutic settings such as the use of inhaled NO, where O2 delivery and Hb functions are altered.