Novel role of smooth muscle B5 reductase in Sickle Cell Disease

摘要：镰状细胞病（SCD）相关的血管病变是多因素的，其发病机制 仍然不完全理解。迄今为止，临床和实验证据都得出结论， NO生物利用度和/或反应性是SCD血管病变的一个促成因素。这项建议旨在 阐明了一种新的还原-氧化（氧化还原）调节机制-CyB 5 R3依赖性还原sGC- 控制血管平滑肌细胞（VSMCs）中NO敏感性及其对血管病变的影响， SCD。重要的是，通过使用从实验室到床边的方法，我们表征了这种信号通路， 以及细胞培养中的功能丧失。我们探讨了这种信号通路对发展的影响， 人源化转基因镰状细胞小鼠（BERK）和移植到 他莫昔芬诱导的Cre-Lox平滑肌特异性CyB 5 R3敲除。最后，我们将扩展这些见解 通过表征CyB 5 R3 T117 S多态性变体功能丧失对 内皮功能我们测试个性化或精准医学方法，以改善患者的健康状况。 患有PH的SCD个体，通过新的sGC调节剂药物靶向响应性Cyb 5 R3基因型。 考虑到sGC在NO信号传导中的决定性作用以及sGC的氧化态可以预测 对新型sGC激活剂和刺激剂药物的反应，我们预计这些研究将 显著影响我们对生物学的理解，精确治疗（为正确的患者提供正确的药物）， 药物遗传学（多态性药物选择）。

Abstract: Vasculopathy associated with Sickle Cell Disease (SCD) is multifactorial and the pathogenesis remains incompletely understood. To date, both clinical and experimental evidence concludes that reduced NO bioavailability and/or responsiveness is a contributing factor to vasculopathy in SCD. This proposal aims to elucidate a novel reduction-oxidation (redox) regulation mechanism – the CyB5R3-depenent reduction of sGC- that controls NO sensitivity in vascular smooth muscle cells (VSMCs) and its impact on vasculopathy and in SCD. Importantly, by using a bench-to-bedside approach, we characterize this signaling pathway with gain and loss of function in cell culture. We explore the impact of this signaling pathway on the development of vasculopathy in the humanized transgenic sickle cell mouse (BERK) and chimeras transplanted into a tamoxifen-inducible Cre-Lox smooth muscle specific CyB5R3 knock-out. Finally we will extend these insights to the bedside by characterizing the effect of loss of function CyB5R3 T117S polymorphic variants on endothelial function. We test a personalized or precision medicine approach to improve the health of individuals with SCD with PH, via the targeting of new sGC modulator drugs to responsive Cyb5R3 genotypes. Considering the defining role of sGC in NO signaling and the fact that the oxidation state of sGC may predict responses to new classes of sGC activator and stimulator medications, we anticipate that these studies will significantly impact our understanding of biology, precision therapeutics (right drug for the right patient) and pharmacogenetics (polymorphism based drug selection).