MRI and NIRS in SS Patients and Mice

SS 患者和小鼠的 MRI 和 NIRS

• 批准号: 7076119
• 负责人: Mary E Fabry
• 金额: $ 18.48万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7076119
• 关键词: arginine; blood circulation; cooperative study; genetically modified animals; hemoglobin F; human subject; hydroxyurea; hypoxia; infrared spectrometry; laboratory mouse; magnetic resonance imaging; microarray technology; oxygen; questionnaires; respiratory gas level; respiratory oxygenation; sickle cell anemia

A primary feature of sickle cell disease are events resulting in low flow, poor perfusion, and blood and tissue hypoxia that are both pre-disposing to and the consequence of vaso-occlusion. We propose to test the limits of the hypothesis that the level of HbF, arginine in diet, and hydroxyurea all affect perfusion and blood oxygenation, albeit through different mechanisms. We will use a combination of Magnetic Resonance Imaging (MRI) and Near Infrared Spectroscopy (NIRS) to measure blood oxygenation, perfusion, and blood volume in human sickle cell patients and our new sickle transgenic mice that we have developed and characterized. At the onset of the grant period, our new Magnetic Resonance Research Center will have been in operation for more than 18 months with state-of-the-art 4 Tesla human and 9.4 Tesla animal systems. We have generated mice expressing exclusively human sickle hemoglobin with three levels of HbF using our previously described sickle constructs, mouse alpha- and beta-globin-knockouts, and three different human gamma-transgenes. We find that, progressive increase in HbF from <3% to 20% to 40% correlated with progressive increase in hematocrit (22% to 34% to 40%), a progressive decrease in reticulocyte count (fi'om 60% to 30% to 13%), and an increase in lifespan (from 45 to 194 to 368 days). Using BOLD-MRI or blood level oxygenation dependent magnetic resonance imaging and T2 mapping, we have demonstrated that transgenic mice expressing high levels of human and beta-s-globin have higher levels of deoxy Hb in brain, liver, and kidney, (areas showing pathology) compared to control mice. We also will measure a battery of other physiological properties including: reticulocytes, CBC, and red cell density, and, in the mice, rotorod performance (a measure of motor co-ordination and stamina) and urine concentrating ability. Finally, we propose !that arginine may ameliorate the symptoms of sickle cell disease and will test this in humans and mice by measurement of flow and oxygenation as described in this Project and transport measurements described in the Arginine Supplementation in Sickle Cell Disease Project. Our long range goal is to demonstrate that these technologies can used for evaluation of pathology and prediction of risk in sickle cell disease patients.

镰状细胞疾病的一个主要特征是导致流量低下，灌注不良以及血液和组织缺氧的事件，这些事件既预先介绍，又是血管肠结牙的后果。我们建议测试HBF，饮食中的精氨酸和羟基脲水平的假设的局限性，都会影响灌注和血液氧合，尽管通过不同的机制。我们将使用磁共振成像（MRI）和近红外光谱法（NIR）的组合来测量人类镰状细胞患者的血液氧合，灌注和血容量以及我们已经开发和表征的新的镰状转基因小鼠。在赠款期开始时，我们的新磁共振研究中心将使用最先进的4个特斯拉人和9.4个特斯拉动物系统运营超过18个月。我们已经使用我们先前描述的镰状构建体，小鼠α-和 β-珠蛋白敲除和三种不同的人类伽马转基因。我们发现，HBF从<3％增加到20％增加到40％与血细胞比容的逐步增加相关（22％到34％到40％），网状细胞计数的逐渐减少（FI'OM 60％至30％至30％至13％），以及寿命增加到45天到368天）。使用BOLD-MRI或血液水平氧合依赖性的磁共振成像和T2映射，我们证明了表达高水平的人和β-S-Globin的转基因小鼠在脑，肝脏和肾脏中具有更高水平的脱氧HB（与对照小鼠相比）。我们还将测量其他生理特性的电池，包括：网状细胞，CBC和红细胞密度，以及在小鼠中，Rotorod性能（运动协调和耐力的量度）和尿液浓缩能力。最后，我们提出！精氨酸可以改善镰状细胞疾病的症状，并通过测量流量和氧合在人类和小鼠中进行测试，如本项目中所述，以及在 镰状细胞疾病项目中补充精氨酸。我们的远距离目标是证明这些技术可以用于评估病理学和镰状细胞病患者风险的预测。