The role of metabolic and hemodynamic reserve in age-related brain vulnerability in pediatric sickle cell anemia

代谢和血流动力学储备在儿童镰状细胞性贫血年龄相关大脑脆弱性中的作用

• 批准号: 10427330
• 负责人: Kristin Guilliams
• 金额: $ 47.29万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10427330
• 关键词: Adult; Affect; African American; Age; Anemia; Area; Blood flow; Brain; Brain Injuries; Brain imaging; Cell Death; Cell physiology; Cerebral Infarction; Cerebrum; Child; Childhood; Chronic; Clinical Treatment; Coupled; Data; Data Set; Databases; Dependence; Development; Ensure; Evolution; Goals; Growth; Growth and Development function; Hemoglobin; Hypoxemia; Image; Imaging Techniques; Infarction; Injury; Intervention; Knowledge; Lead; Link; Magnetic Resonance Imaging; Measures; Metabolic; Metabolism; Modeling; Neurological outcome; Only Child; Oxygen; Physiological; Population; Prevention therapy; Resolution; Risk; Role; Sickle Cell; Sickle Cell Anemia; Signal Transduction; Stroke prevention; Technology; Thick; Thinness; Transfusion; age related; age stratification; arteriole; brain dysfunction; brain volume; cellular imaging; cerebrovascular; cohort; cost; experience; follow-up; gray matter; hemodynamics; high risk; hydroxyurea; impaired brain development; improved; innovation; personalized medicine; sex; treatment strategy; white matter

PROJECT ABSTRACT If oxygen supply to the brain does not match its demands, cellular functions are impeded and can lead to cell death. A margin is created between oxygen supply and brain demand by metabolic and hemodynamic reserves. Our preliminary data show that children may have less reserve due to the critical, but costly energy demands of brain growth and maturation. We have shown that lower oxygen supply (hypoxemia) also decreases reserves, and during childhood, may result in impaired brain growth and development. Children with sickle cell anemia (SCA) have chronic hypoxemia due to reduced hemoglobin. Children with SCA have smaller brain volumes and decreased cortical thickness than unaffected children. The intersection of hypoxemia and brain development is poorly understood, impeding our ability to optimize brain development and neurologic outcomes in children with hypoxemia. The goal of this project is to identify physiologic mechanisms of vulnerability and age-dependent consequences of hypoxemia. Our central hypothesis is that the high cerebral metabolic demand in younger children decreases oxygen reserve, resulting in an age-dependent increased risk for impaired brain growth in children with lower oxygen supply. First, we will assess normal developmental changes in metabolic and hemodynamic reserve in 80 healthy children ages 4-21 to determine age-dependence of reserves (Aim 1). Next, we will determine the effects of hypoxemia on metabolic and hemodynamic reserves and the consequence of hypoxemia on brain development. We will compare 40 children with SCA and 40 age and sex-matched controls at baseline and 3 year follow-up imaging, and examine cortical thickness changes in the two cohorts (Aim 2). Finally, we will evaluate whether oxygen reserve increased through hydroxyurea treatment in an SCA cohort impacts long-term brain development. We will utilize a large sickle cell database with 16 years of brain imaging to compare cortical thickness maturation and total brain volumes between treated and untreated children (Aim 3). Determining the age-dependence of hypoxemic vulnerability and its effect on brain development will allow us to personalize treatment strategies for children at high risk for neurodevelopmental injury to be more aggressive during periods of highest vulnerability.

项目摘要 如果向大脑的氧气供应不符合其需求，则会阻碍细胞功能，并且 会导致细胞死亡。通过氧气供应和大脑需求之间的利润率 代谢和血液动力学储量。我们的初步数据表明，儿童可能较少 由于对大脑生长和成熟的重要能源需求，因此预备役。我们有 表明较低的氧气供应（低氧血症）也减少了储量，在儿童时期， 可能导致脑生长和发育受损。患有镰状细胞贫血（SCA）的孩子 由于血红蛋白降低，患有慢性低氧血症。 SCA儿童的大脑较小 与未受影响的儿童相比，体积和皮质厚度减少。交集 低氧血症和大脑发育知之甚少，阻碍了我们优化大脑的能力 缺氧儿童的发育和神经结局。这个项目的目标是 确定脆弱性和年龄依赖性后果的生理机制 低氧血症。我们的中心假设是年轻的大脑代谢需求很高 儿童减少氧气储备，从而导致年龄增加的风险增加 氧气供应较低的儿童的大脑生长。首先，我们将评估正常发展 80岁的4-21岁健康儿童的代谢和血流动力储备的变化以确定 储量的年龄依赖性（目标1）。接下来，我们将确定低氧血症对 代谢和血液动力学储备以及低氧血症对大脑的后果 发展。我们将比较40个患有SCA和40岁的儿童，并且在 基线和3年随访成像，并检查两者的皮质厚度变化 队列（目标2）。最后，我们将评估氧储备是否通过 SCA队列中的羟基脲治疗会影响长期的大脑发育。我们将利用一个 具有16年脑成像的大型镰状细胞数据库比较皮质厚度 治疗和未经治疗的儿童之间的成熟和总脑体积（AIM 3）。确定 低氧脆弱性及其对大脑发育的影响的依赖性将使我们 个性化神经发育损伤高风险儿童的治疗策略 在最高脆弱性期间更具侵略性。