Project 2: RBC Irradiation and Anemia Trigger Gut Injury in Preterm Infants

坏死性小肠结肠炎（NEC）是一种以肠道炎症迅速发展为特征的疾病， 通常导致肠坏死，是新生儿发病和死亡的主要原因。NEC 发病机制知之甚少，也没有诊断测试来预测哪些婴儿会发展 NEC;此外，没有有效的预防战略。最近的研究发现， 红细胞（RBC）输注是极低出生体重（ELBW）婴儿的常见疗法， 发生输血相关NEC（TR-NEC）的危险因素和潜在致病因素， 定义为RBC输注后48小时内发生NEC。然而，生物学和临床 RBC TR-NEC的决定因素仍然知之甚少。 我们的研究计划将招募220名ELBW婴儿，这是第一个前瞻性、大型、多中心队列研究。 本研究旨在研究以下因素导致NEC发生的病理生理机制 红细胞输血。我们的总体假设是，照射红细胞单位，然后延长 储存扰乱RBC代谢/功能，导致反常的微血管收缩，组织 缺氧和TR-NEC在已经受损的肠道氧合的输血婴儿中的应用 贫血我们的三个具体目标将测试这一假设的关键方面。这项研究将利用创新的 研究TR-NEC的方法，包括代谢组学（目标1和2），近红外光谱（NIRS） 其是肠系膜局部氧饱和度的体内非侵入性测量（MES-rSO 2;目的 1和3），以及体外RBC功能研究（目的2）。这项拟议的研究将填补关键的知识空白 红细胞保存时间和照射对新生儿肠道损伤的影响。此外，这些数据将 指导新干预措施的开发，例如使用NIRS识别易感婴儿，限制IST 储存的RBC产品，并使用代谢物生物标志物来预测RBC的安全性。 本项目涉及P01的中心主题，因为ELBW早产儿是一个群体， 在既往输注RBC的情况下易发生TR-NEC。该项目相互作用 与项目1，3和4，通过识别与不良反应相关的代谢生物标志物， 输血事件。此外，核心A（监管批准、样本储存库）、核心B （代谢组学）和核心C（生物统计学）在拟议的研究中大量使用。

Necrotizing enterocolitis (NEC), a disease characterized by rapid development of intestinal inflammation, often resulting in gut necrosis, is a leading cause of neonatal morbidity and mortality. NEC pathogenesis is poorly understood, and there are no diagnostic tests to predict which infants will develop NEC; furthermore, there are no effective prevention strategies. Recent studies have identified red blood cell (RBC) transfusion, a common therapy in extremely low birth weight (ELBW) infants, as an important risk factor and potential causative factor in the development of transfusion-related NEC (TR-NEC), defined as NEC developing within 48 hours of a RBC transfusion. However, biologic and clinical determinants of RBC TR-NEC remain poorly understood. Our proposed study will enroll 220 ELBW infants and be the first prospective, large, multicenter cohort study to investigate the pathophysiologic mechanisms that underlie the development of NEC following RBC transfusion. Our overarching hypothesis is that irradiation of RBC units followed by prolonged storage perturbs RBC metabolism/function, leading to paradoxical microvascular vasoconstriction, tissue hypoxia and TR-NEC in transfused infants with already impaired gut oxygenation due to significant anemia. Our three specific aims will test key aspects of this hypothesis. This study will utilize innovative methods to study TR-NEC, including metabolomics (Aims 1 and 2), near-infrared spectroscopy (NIRS) which is an in vivo non-invasive measure of mesenteric regional saturation of oxygen (MES-rSO2; Aims 1 and 3), and in vitro RBC functional studies (Aim 2). This proposed study will fill key knowledge gaps regarding the effects of RBC storage time and irradiation on neonatal gut injury. Further, these data will guide development of new interventions, such as using NIRS to identify susceptible infants, limiting IST of stored RBC products, and using metabolite biomarkers to predict RBC safety. This project addresses the P01 central theme since ELBW preterm infants are a population vulnerable to the development of TR-NEC with antecedent RBC transfusion(s). This project interacts with Projects 1, 3, and 4 by identifying metabolic biomarkers that are associated with adverse transfusion events. Additionally Core A (regulatory approvals, sample repository), Core B (metabolomics), and Core C (biostatistics) are utilized heavily in the proposed studies.