Somatosensory Modulation of Salivary Gene Expression and Oral Feeding in Preterm Infants

 描述(由申请人提供)：极早产儿(EPI)(妊娠28周)对多种重大短期和长期医学并发症的易感性增加，这些并发症显著推迟了出院所需的基本里程碑的发展，如口服喂养。此外，与胎龄匹配的对照组相比，患有支气管肺发育不良(BPD)的婴儿更有可能出现口腔喂养困难。尽管在这一高危人群中口腔喂养困难的频率很高，但目前还没有客观的评估工具来预测婴儿何时可以安全地用口腔喂养，只有有限的干预策略来改善喂养行为。这项研究提案的总体目标是将共同投资伙伴Steven Barlow博士和Jill Maron博士的专业知识结合起来，开发一种创新的、新颖的、个性化的和综合的方法，直接满足计划免疫人群对口腔喂养治疗策略的重要需求。在这项多中心试验中，180名EPI将从三个新生儿重症监护病房(东北林肯的ChiHealth St.Elizabeth；马萨诸塞州波士顿的塔夫茨医疗中心；以及加利福尼亚州圣何塞的圣克拉拉谷医疗中心)招募。婴儿将随机接受巴洛实验室先前开发的脉冲口腔体感刺激(PULSE NTrainer(R))，或从怀孕后30周开始接受SHAM(盲目安抚奶嘴)，直到完成全部口服喂养或出院。同时采集系列唾液样本(n=2/周)，以检测六种生物标志物(AMPK、NPY2R、NPHP4、WNT3、PLXNA1、PLXNA3)的基因表达谱，这些标志物以前被Maron实验室证明与早产儿的口服喂养成功有关。在目标1中，我们将测试一种假设，即接受脉冲NTrainer(R)干预的婴儿实现完全口服喂养的持续时间将缩短，他们的唾液基因表达谱将与喂养成功相关。婴儿将根据他们的胎龄、性别和BPD状况进行分层。在AIM#2中，将对AIM#1的临床和基因表达数据进行计算分析，以确定对脉冲NTrainer(R)干预的应答者和无应答者，并确定婴儿最可能从干预中受益的神经发育的关键时刻。最后，在Aim#3中，婴儿将在18-24个月的PCA时接受Bayley III发育筛查，以评估脉冲NTrainer(R)对喂养行为和神经发育的长期影响，以及新生儿唾液基因表达谱预测儿童以后损害的准确性。还将使用NICHD NRN 18个月喂养-生长-营养问卷对婴儿进行评估，以进一步了解脉冲NTrainer(R)对长期生长和喂养行为的影响。

 DESCRIPTION (provided by applicant): Extremely preterm infants (EPIs) (< 28 weeks' gestation) have increased susceptibility for multiple significant short- and long-term medical complications that significantly delay the development of essential milestones, such as oral feeding, required for discharge. Further, infants who develop bronchopulmonary dysplasia (BPD) are at even greater risk for oral feeding difficulties compared to gestationally aged matched controls. Despite the frequency of oral feeding difficulties in this at-risk population, there currently exists no objective assessment tool to predict when an infant may safely feed by mouth and only limited intervention strategies to improve feeding behavior. The overall goal of this research proposal is to pair the expertise of Co-PIs Drs. Steven Barlow and Jill Maron to develop an innovative, novel, personalized and integrative approach that directly addresses the important need for oral feeding treatment strategies for the EPI population. In this multicenter trial, 180 EPIs will be enrolled from three neonatal intensive care units (CHI Health St. Elizabeth, Lincoln, NE; Tufts Medical Center, Boston, MA; and Santa Clara Valley Medical Center, Santa Jose, CA). Infants will be randomized to receive either PULSED orocutaneous somatosensory stimulation (PULSED NTrainer(r)) previously developed in the Barlow Laboratory, or SHAM (blind pacifier) starting at 30 weeks' post- conceptional age (PCA) up to the achievement of full oral feeds or discharge home. Serial salivary samples (n=2/week) will be obtained concomitantly to examine the gene expression profiles of six biomarkers (AMPK, NPY2R, NPHP4, WNT3, PLXNA1, PLXNA3) previously shown by the Maron Laboratory to be associated with oral feeding success in the premature newborn. In Aim #1, we will test the hypothesis that infants who received PULSED NTrainer(r) intervention will have a shortened duration of time to achieve full oral feeds and that their salivary gene expression profiles will correlate with feeding success. Infants will be stratified based upon their gestational age, sex, and BPD status. In Aim #2, computational analyses of both clinical and gene expression data from Aim #1 will be performed to identify responders and non-responders to the PULSED NTrainer(r) intervention and to identify critical times in neurodevelopment when infants may most benefit from the intervention. Finally in Aim #3, infants will undergo Bayley III Developmental Screen at 18-24 months' PCA to assess both the long-term effect of the PULSED NTrainer(r) on feeding behavior and neurodevelopment and the accuracy of neonatal salivary gene expression profiles to predict impairments later in childhood. Infants will also be assessed with the NICHD NRN 18-month Feeding-Growth-Nutrition Questionnaire to further our understanding of the PULSED NTrainer(r) on long-term growth and feeding behavior.