Novel Complementary Therapy for Preterm Infants

描述（由申请人提供）：尽管世界范围内的健康状况有所改善，医疗实践也有所进步，但早产的发生率在全球几乎每个地区都在持续上升，在美国，早产占所有活产婴儿的近15%。与极低出生体重婴儿数量增加相关的是几种既危及生命又代价高昂的医疗状况。其中一种情况是坏死性小肠结肠炎（NEC），这是新生儿重症监护病房发病率和死亡率的主要原因，是一种目前没有药物治疗的疾病。该应用程序的一个重要特点是研究烟酰胺（已知的PARP抑制剂）作为NEC的潜在治疗剂。我们将开展临床前研究，以确定机制作用并确定潜在疗效的最佳条件。这些研究将使用相关的人胎儿肠上皮细胞和新生儿肠损伤动物模型来验证我们的工作假设。我们的第一阶段目标是：AIM 1：利用人类新生儿肠细胞损伤和恢复的临床前模型确定烟酰胺的浓度-效应关系和信号活性；AIM 2：在我们建立的NEC大鼠模型中评估烟酰胺的安全性和给药方案，并证明烟酰胺在我们建立的NEC新生大鼠模型中减轻肠道损伤的原理。这个第一阶段项目的具体目标是证明烟酰胺用于NEC预防和/或治疗的原理证明。公共卫生相关性：尽管世界范围内的健康状况有所改善，医疗实践也有所进步，但早产的发生率在全球几乎每个地区都在持续上升，在美国，早产占所有活产婴儿的近15%。与极低出生体重婴儿数量增加相关的是几种既危及生命又代价高昂的医疗状况。其中一种情况是坏死性小肠结肠炎（NEC），这是新生儿重症监护病房发病率和死亡率的主要原因，是一种目前没有药物治疗的疾病。我们有初步证据表明烟酰胺是NEC的潜在治疗剂。我们将利用相关的人胎儿肠上皮细胞和新生儿肠损伤动物模型开展临床前研究，以确定其机制作用并确定潜在疗效的最佳条件。

DESCRIPTION (provided by applicant): Despite improvements in worldwide health and advances in medical practice the incidence of preterm birth continues to rise in virtually every region of the globe and is accounts for nearly 15% of all live births in the United States. Associated with this increased population of very low birth-weight infants are several medical conditions that are both life threatening and costly. One of these conditions is necrotizing enterocolitis (NEC), a major cause of morbidity and mortality in neonatal intensive care units, is a disease for which there is currently no medical treatment. An important feature of this application is the investigation of nicotinamide (known inhibitor of PARP) as a potential therapeutic agent for NEC. We will carry out preclinical studies to define mechanistic actions and identify optimal conditions for potential efficacy. These studies will use relevant human fetal intestinal epithelial cells and animal models of newborn intestinal injury to test our working hypothesis. Our Phase 1 aims are: AIM 1: Define concentration-effect relationships and signaling activities of Nicotinamide using a preclinical model of human neonatal enterocyte injury and restitution and AIM 2: Evaluate the safety of and dosing regimen for nicotinamide in our established rat model of NEC and demonstrate proof of principle for attenuation of intestinal injury in our established newborn rat model of NEC by Nicotinamide. The specific goal of this phase 1 project is to demonstrate the proof of principle for the use of nicotinamide for NEC prevention and/or treatment. PUBLIC HEALTH RELEVANCE: Despite improvements in worldwide health and advances in medical practice the incidence of preterm birth continues to rise in virtually every region of the globe and is accounts for nearly 15% of all live births in the United States. Associated with this increased population of very low birth-weight infants are several medical conditions that are both life threatening and costly. One of these conditions is necrotizing enterocolitis (NEC), a major cause of morbidity and mortality in neonatal intensive care units, is a disease for which there is currently no medical treatment. We have preliminary evidence to demonstrate that nicotinamide is a potential therapeutic agent for NEC. We will carry out preclinical studies to define mechanistic actions and identify optimal conditions for potential efficacy using relevant human fetal intestinal epithelial cells and animal models of newborn intestinal injury.