Novel role of smooth muscle B5 reductase in Sickle Cell Disease

平滑肌 B5 还原酶在镰状细胞病中的新作用

基本信息

批准号：
9749982
负责人：
Adam Carl Straub
金额：
$ 61万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9749982
关键词：
Ablation African American Age Animals Biological Availability Biology Blood Pressure Blood Vessels Blood flow Bone Marrow Diseases Cardiovascular Physiology Cell Culture Techniques Cells Cessation of life Chimera organism Clinical Collaborations Cre-LoxP Critical Pathways Cyclic GMP Data Development Disodium Salt Nitroprusside Endothelium Erythrocytes Etiology Evaluation Exposure to Gene Frequency Generations Genetic Genetic Polymorphism Genotype Health Heme Heme Iron Hemoglobin Human Impairment In Vitro Individual Infusion procedures Intra-Arterial Infusions Iron Knock-out Laboratories Link Lung Measurement Measures Mediating Medicine Methemoglobin Morbidity - disease rate Mus Mutation Nitric Oxide Nitric Oxide Donors Oxidases Oxidation-Reduction Oxides Oxidoreductase Pathogenesis Patient Rights Patients Peroxidases Pharmaceutical Preparations Pharmacogenetics Pharmacogenomics Pharmacology Plasma Point Mutation Precision therapeutics Pulmonary Hypertension Reaction Reactive Oxygen Species Regulation Resistance Risk Risk Factors Role Sickle Cell Sickle Cell Anemia Signal Pathway Signal Transduction Smooth Muscle Smooth Muscle Myocytes Soluble Guanylate Cyclase Systemic hypertension Tamoxifen Testing Transgenic Organisms Transplantation Transplantation Chimera Variant Vascular Diseases Vascular Smooth Muscle base bench to bedside cGMP production cell type cytochrome b5 reductase design endophenotype endothelial dysfunction gain of function guanylate hemodynamics improved in vivo insight iron (III) reductase knock-down loss of function mimetics novel oxidation personalized medicine placebo controlled study precision medicine predicting response response systolic hypertension

项目摘要

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).

摘要：与镰状细胞疾病（SCD）相关的血管病是多因素和发病机理仍然不完全理解。迄今为止，临床和实验证据都得出结论，减少了没有生物利用度和/或反应能力是SCD中血管病的原因。该建议旨在阐明一种新型还原氧化（氧化还原）调节机制 - cyb5r3-替代SGC-的降低控制血管平滑肌细胞（VSMC）及其对血管病和其影响的敏感性 scd。重要的是，通过使用台式卧式方法，我们以增益来表征此信号通路和细胞培养中功能的丧失。我们探讨了此信号通路对发展的影响人源化转基因镰状细胞小鼠（Berk）和嵌合体中的血管病被移植到一个他莫昔芬诱导的Cre-lox平滑肌特异性CYB5R3敲除。最后，我们将扩展这些见解通过表征功能损失CYB5R3 T117S多态性变体的影响到床边内皮功能。我们测试了一种个性化或精确的医学方法，以改善具有pH的SCD的个体是通过将新的SGC调节药物靶向响应式CYB5R3基因型的。考虑到SGC在无信号传导中的定义作用以及SGC的氧化状态可能预测的事实对新类SGC激活剂和刺激剂药物的反应，我们预计这些研究将会显着影响我们对生物学，精确疗法（适合合适患者的正确药物）和药物遗传学（基于多态性的药物选择）。