MRI and NIRS in SS Patients and Mice

SS 患者和小鼠的 MRI 和 NIRS

• 批准号: 7406849
• 负责人: Mary E Fabry
• 金额: $ 18.46万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7406849
• 关键词: Acute; Adult; Affect; Age; Animals; Area; Arginine; Arts; Basic Science; Blood; Blood Vessels; Blood Volume; Blood flow; Brain; Chronic; Collaborations; Diet; Dose; Enzymes; Erythrocytes; Evaluation; Event; Globin; Goals; Grant; Hematocrit procedure; Hemoglobin; Human; Hypoxia; Image; Kidney; Kidney Concentrating Ability; Knock-out; Liver; Longevity; Magnetic Resonance; Magnetic Resonance Imaging; Magnetism; Maps; Measurement; Measures; Modeling; Monitor; Motor; Mus; Near-Infrared Spectroscopy; Operative Surgical Procedures; Organ; Outcome; Pathology; Patients; Performance; Perfusion; Perfusion Weighted MRI; Physiological; Property; Range; Research; Reticulocyte count; Reticulocytes; Risk; Severities; Sickle Cell; Sickle Cell Anemia; Sickle Hemoglobin; Stroke; Supplementation; Symptoms; System; Technology; Testing; Tissues; Transgenes; Transgenic Mice; Treatment Protocols; Upper arm; Vasodilator Agents; age group; base; beta Globin; blood oxygen level dependent; blood perfusion; day; density; hydroxyurea; improved; infrared spectroscopy; mouse model; response; sex; sickling

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.

镰状细胞病的主要特征是导致低流量、灌注不良以及血液和组织缺氧的事件，这些事件都是血管闭塞的诱发因素和后果。我们建议测试假设的限制，即HbF，饮食中的精氨酸和羟基脲的水平都会影响灌注和血氧，尽管是通过不同的机制。我们将使用磁共振成像（MRI）和近红外光谱（NIRS）的组合来测量人类镰状细胞患者和我们开发和表征的新型镰状转基因小鼠的血氧，灌注和血容量。在拨款期开始时，我们的新磁共振研究中心将使用最先进的4特斯拉人体和9.4特斯拉动物系统运行超过18个月。我们已经使用我们先前描述的镰状构建体产生了仅表达具有三种HbF水平的人镰状血红蛋白的小鼠，小鼠α-和 β-珠蛋白敲除和三种不同的人类γ-转基因。我们发现，HbF从<3%到20%到40%的逐渐增加与血细胞比容的逐渐增加（22%到34%到40%）、网织红细胞计数的逐渐减少（从60%到30%到13%）和寿命的增加（从45天到194天到368天）相关。使用BOLD-MRI或血液水平氧合依赖性磁共振成像和T2映射，我们已经证明，与对照小鼠相比，表达高水平人类和β-s-珠蛋白的转基因小鼠在脑、肝和肾（显示病理学的区域）中具有更高水平的脱氧Hb。我们还将测量一系列其他生理特性，包括：网织红细胞、CBC和红细胞密度，以及小鼠的旋转棒性能（运动协调和耐力的测量）和尿液浓缩能力。最后，我们求婚！精氨酸可以改善镰状细胞病的症状，并将在人类和小鼠中通过测量本项目中描述的流量和氧合以及 镰状细胞病的精氨酸补充项目。我们的长期目标是证明这些技术可以用于镰状细胞病患者的病理学评估和风险预测。