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

摘要 在这份补充材料（PA-18-658：性/性别影响研究的行政补充材料）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含量的影响 代谢作为儿童卒中发病率性别差异的机制。脑氧代谢 CMRO 2是脑血流量（CBF）、氧摄取分数（OEF）和动脉血氧的乘积 含量（CaO 2）。CMRO 2的组分，即OEF升高，预示着成人缺血性卒中。我父母 儿童镰状细胞病脑氧代谢的K23依赖性和卒中风险 （1 K23 NS 099472 -01）”假设CBF和OEF的发育变化是年龄依赖性 镰状细胞病（SCD）儿童缺血性脆弱性。除了年龄，男性也是一个 未被充分研究的儿童中风危险因素。在SCD中，男性和 为预防中风而接受输血的女性人数不成比例地高，这引起了人们的关注， 患有SCD的女性可能过度暴露于输血。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的预防、诊断和治疗”。这里我 我建议在我以前的工作的基础上，了解性别依赖的发育变化是否 CBF和OEF的变化为儿童卒中发病率的性别差异提供了潜在的机制。我 我不能将性别作为变量纳入我的父母K23，作为CMRO 2性别差异的初步数据 在儿童中并不存在。由于正电子发射断层扫描（PET）历来是主要的模态 为了研究CMRO 2和PET固有的辐射，很少有关于儿童CMRO 2的研究发表。那些 出版的研究性别差异的主题太少。CBF在儿童时期是动态的， 最近的研究表明，CBF的发展轨迹在男性和女性之间存在差异，但OEF值在男性和女性之间存在差异。 童年是未知的。在我资助的研究过程中，我发现OEF是年龄依赖性的， 使用新型磁共振成像序列，在年幼儿童中观察到更高的值。我的数据 表明，但没有足够的力量来证实，OEF也是性别依赖的。这些补充活动将 模型CMRO 2及其组件，以确定性别是否显著影响年龄依赖性氧 代谢和实现国家卫生研究院战略计划的既定目标，“研究老化中的性别差异， 过程”在生命的第一个几十年，以及项目的声明利益“，旨在增加机械 了解性别差异”。这项工作的成功将推进我们对缺血性损伤的认识 为SCD儿童脑卒中的性别差异提供了机制依据， 可能最终导致SCD女孩和妇女的输血减少，所有儿童的中风减少。

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.