Age-Dependence of Cerebral Oxygen Metabolism and Stroke Risk in Pediatric Sickle Cell Disease

儿童镰状细胞病脑氧代谢和中风风险的年龄依赖性

• 批准号: 9673357
• 负责人: Kristin Guilliams
• 金额: $ 7.02万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9673357
• 关键词: Address; Administrative Supplement; Adolescence; Adult; Age; Aging-Related Process; Area; Award; Blood Transfusion; Brain; Cerebrovascular Circulation; Cerebrum; Child; Childhood; Childhood stroke; Chronic; Data; Dependence; Development; Diagnostic; Disease; Exposure to; Female; Foundations; Functional disorder; Funding; Future; Gender; Goals; Human Biology; Ischemic Stroke; Knowledge; Lead; Life; Magnetic Resonance Imaging; Measures; Metabolic; Metabolism; Methods; Modality; Modeling; Morbidity - disease rate; Neurologic; Oxygen; Oxygen Consumption; Parents; Pediatric Brain Injury; Population; Positron-Emission Tomography; Prevention strategy; Puberty; Publishing; Radiation; Research; Research Personnel; Risk; Risk Factors; Role; Sex Characteristics; Sickle Cell Anemia; State Interests; Strategic Planning; Stroke; Stroke prevention; Techniques; Testing; Therapeutic; Tissues; Transfusion; United States National Institutes of Health; Woman; Women' s Health; Work; age related; base; boys; career development; cohort; experience; girls; high risk; individualized medicine; individualized prevention; male; mortality; novel; screening; sex; stroke incidence; stroke risk; stroke therapy; success; young adult

ABSTRACT In this supplement (PA-18-658: Administrative Supplement for Research on Sex/Gender Influences), I will expand my cohort of children and young adults to examine sex influence on age-dependent cerebral oxygen metabolism as a mechanism for sex-differences of pediatric stroke incidence. Cerebral oxygen metabolism (CMRO2) is the product of cerebral blood flow (CBF), oxygen extraction fraction (OEF) and arterial oxygen content (CaO2). Components of CMRO2, i.e. an elevated OEF, herald ischemic stroke in adults. My parent K23 “Age-dependence of cerebral oxygen metabolism and stroke risk in pediatric sickle cell disease (1K23NS099472-01)” hypothesizes developmental changes of CBF and OEF underlie the age-dependent ischemic vulnerability in children with sickle cell disease (SCD). In addition to age, male sex is an understudied risk factor for pediatric stroke. In SCD, the overwhelmingly higher stroke incidence in males and disproportionately high number of females receiving transfusions for stroke prevention raise the concern that females with SCD may be over-exposed to blood transfusions. Understanding the mechanisms for of stroke incidence discrepancies is imperative to address Goal 3 of the NIH Strategic Plan for Women’s Health Research, “to actualize personalized prevention, diagnostics, and therapeutics for girls and women”. Here, I propose to build upon my prior work to understand whether sex-dependent developmental changes of CBF and OEF provide potential mechanisms for sex differences in pediatric stroke incidence. I could not have included sex as a variable in my parent K23, as preliminary data for sex differences of CMRO2 in children did not exist. Due to positron-emission tomography (PET) historically being the primary modality to study CMRO2, and radiation inherent with PET, few studies are published about CMRO2 in children. Those published have too few subjects to examine sex-differences. CBF is known to be dynamic in childhood, and recent work shows developmental trajectories of CBF differ between males and females, but OEF values in childhood were unknown. In the course of my funded research, I found that OEF is age-dependent, with higher values observed in younger children, using novel magnetic resonance imaging sequences. My data suggests, but is underpowered to confirm, that OEF is also sex-dependent. These supplemental activities will model CMRO2 and its components to determine if sex significantly impacts age-dependent oxygen metabolism and achieve the stated objective of the NIH Strategic Plan to “study sex differences in the aging process” in the first decades of life, as well as the stated interest of projects “aimed at increasing mechanistic understanding of sex differences”. Success in this work will advance our knowledge of ischemic vulnerability in children, and provide mechanistic foundations for sex-differences of stroke in children with SCD, which may ultimately lead to fewer blood transfusions in girls and women with SCD and fewer strokes in all children.

抽象的 在本补充文件（PA-18-658：性/性别影响研究行政补充文件）中，我将 扩大我的儿童和年轻人队列，以检查性别对年龄依赖性脑氧的影响 代谢作为儿童卒中发病率性别差异的机制。脑氧代谢 (CMRO2) 是脑血流量 (CBF)、氧提取分数 (OEF) 和动脉氧的乘积 含量（CaO2）。 CMRO2 的组成部分，即 OEF 升高，预示着成人缺血性中风。我的父母 K23“儿童镰状细胞病脑氧代谢和中风风险的年龄依赖性 (1K23NS099472-01)”假设 CBF 和 OEF 的发育变化是年龄依赖性的基础 镰状细胞病（SCD）儿童的缺血脆弱性。除了年龄之外，男性的性别也是一个因素 儿童中风的危险因素尚未得到充分研究。在 SCD 中，男性和女性的中风发病率极高 为预防中风而接受输血的女性人数过多，引起了人们的关注： 患有 SCD 的女性可能过度输血。了解中风的机制 发病率差异对于实现 NIH 妇女健康战略计划的目标 3 至关重要 研究“为女孩和妇女实现个性化预防、诊断和治疗”。在这里，我 建议以我之前的工作为基础来了解性别依赖性发育变化是否 CBF 和 OEF 的研究提供了儿童卒中发病率性别差异的潜在机制。我 无法将性别作为我父母 K23 中的变量，作为 CMRO2 性别差异的初步数据 在儿童中不存在。由于正电子发射断层扫描 (PET) 历来是主要模式 为了研究 CMRO2 和 PET 固有的辐射，很少有关于儿童 C​​MRO2 的研究发表。那些 已发表的研究对象太少，无法研究性别差异。众所周知，CBF 在童年时期是动态的，并且 最近的研究表明，男性和女性的 CBF 发展轨迹不同，但 OEF 值 童年是未知的。在我资助的研究过程中，我发现 OEF 与年龄有关， 使用新型磁共振成像序列在年幼的儿童中观察到更高的值。我的数据 表明，但没有足够的证据证实，OEF 也是性别依赖性的。这些补充活动将 模型 CMRO2 及其组件，以确定性别是否显着影响年龄依赖性氧气 代谢并实现 NIH 战略计划的既定目标“研究衰老过程中的性别差异” 生命最初几十年的“过程”，以及“旨在增加机械性”的项目的既定兴趣 了解性别差异”。这项工作的成功将增进我们对缺血脆弱性的了解 并为 SCD 儿童中风的性别差异提供机制基础， 最终可能会减少患有 SCD 的女孩和妇女的输血，并减少所有儿童的中风。