Novel Complementary Therapy for Preterm Infants

描述(申请人提供)：尽管全球健康状况有所改善，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继续上升，占美国所有活产婴儿的近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疾病。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，目前还没有药物治疗。这一应用的一个重要特征是研究烟酰胺(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类胎儿肠道上皮细胞和新生儿肠道损伤的动物模型来验证我们的工作假设。我们的第一阶段目标是：目标1：使用人类新生儿肠细胞损伤和修复的临床前模型来确定烟酰胺的量效关系和信号活性，以及目标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，并证明我们建立的NEC模型中烟酰胺减轻肠道损伤的原理证据。该第一阶段项目的具体目标是证明将烟酰胺用于NEC预防和/或治疗的原则证据。公共卫生相关性：尽管全球健康状况有所改善，医疗实践也有所进步，但全球几乎每个地区的早产发生率都在继续上升，占美国所有活产婴儿的近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疾病。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，目前还没有药物治疗。我们有初步证据表明，烟酰胺是一种潜在的NEC治疗剂。我们将利用相关的人类胎儿肠道上皮细胞和新生儿肠道损伤的动物模型，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。

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.