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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：
9533418
负责人：
Adam Carl Straub
金额：
$ 60.77万
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 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9533418
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 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 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：与镰刀细胞病相关的血管病变是多因素的，其发病机制是多因素的仍然没有完全被理解。到目前为止，临床和实验证据都得出结论，无生物利用度和/或反应性是SCD血管病变的一个促成因素。这项建议旨在阐明一种新的氧化还原调节机制--CyB5R3依赖的sGC还原。它不能控制血管平滑肌细胞(VSMCs)的敏感性及其对血管病变的影响 SCD。重要的是，通过使用工作台到床边的方法，我们用增益来描述这一信号通路以及细胞培养中功能的丧失。我们探讨了这一信号通路在糖尿病的发生发展中的作用。人源化转基因镰状细胞小鼠(BERK)和嵌合体移植到小鼠体内的血管病变他莫昔芬诱导的Cre-Lox平滑肌特异性CyB5R3基因敲除。最后，我们将扩展这些见解通过表征功能丧失的CyB5R3 T117S多态变异对内皮功能。我们测试一种个性化或精准的医疗方法，以改善通过靶向新的sGC调节剂药物来响应Cyb5R3基因，从而使患有慢性阻塞性肺疾病的患者获得更好的治疗效果。考虑到sGC在NO信号转导中的决定作用，以及sGC的氧化状态可以预测对新的sGC激活剂和刺激剂药物的反应，我们预计这些研究将极大地影响了我们对生物学、精确疗法(针对正确的患者使用正确的药物)和药物遗传学(基于多态的药物选择)。