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）对多种显著的短期和长期医学并发症的易感性增加，这些并发症显著延迟了出院所需的重要里程碑（如经口喂养）的发展。此外，与胎龄匹配的对照组相比，患有支气管肺发育不良（BPD）的婴儿发生经口喂养困难的风险更大。尽管在这一高危人群中经常发生经口喂养困难，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经口喂养，只有有限的干预策略来改善喂养行为。该研究提案的总体目标是将Co-PI Steven Barlow博士和Jill Maron博士的专业知识结合起来，开发一种创新，新颖，个性化和综合的方法，直接解决EPI人群口服喂养治疗策略的重要需求。在这项多中心试验中，将从三个新生儿重症监护病房（CHI Health St. Elizabeth，林肯，NE; Tufts Medical Center，Boston，MA;和Santa Clara Valley Medical Center，Santa Jose，CA）入组180名EPI。婴儿将随机接受先前在Barlow实验室开发的脉冲口皮体感刺激（PULSED NTrainer（r））或SHAM（盲用安抚奶嘴），从受孕后30周龄（PCA）开始，直至实现完全经口进食或出院回家。将同时获得系列唾液样本（n=2/周），以检查Maron实验室先前显示与早产儿经口喂养成功相关的6种生物标志物（AMPK、NPY 2 R、NPHP 4、WNT 3、PLXNA 1、PLXNA 3）的基因表达谱。在目标#1中，我们将检验以下假设：接受PULSED NTrainer（r）干预的婴儿实现完全经口进食的时间缩短，其唾液基因表达谱与喂养成功相关。婴儿将根据胎龄、性别和BPD状态进行分层。在目标#2中，将对目标#1的临床和基因表达数据进行计算分析，以确定PULSED NTrainer（r）干预的应答者和非应答者，并确定婴儿可能从干预中获益最多的神经发育关键时期。最后，在目标3中，婴儿将在18-24个月PCA时接受Bayley III发育筛查，以评估PULSED 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后期损伤的准确性。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PULSED 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.