Neonatal Stress in Very Preterm Infants: Longitudinal Effects on Epigenetics and Neurodevelopment

项目摘要/摘要 在美国，每10个出生的婴儿中就有一个会受到早产的影响，导致严重的发病率和经济损失 成本。早产儿(胎龄32周)会增加受损的风险。 神经发育。VPT婴儿经历了更大的生理压力，而他们的照顾者经历了 心理压力增加--两者都与神经发育受损有关。表观遗传 修饰被认为是VPT中生理应激和神经发育的一种可能机制。 婴儿。建议的研究的主要目的是确定新生儿生理的机制 应激诱导表观遗传修饰，从而导致神经发育受损，以及照顾者如何 窘迫缓和新生儿纵向生理应激与神经发育的关系 结果。具体地说，拟议的研究旨在(1)创建和验证新的新生儿指数 VPT婴儿的生理应激；(2)确定新生儿生理应激对表观遗传学的影响 VPT婴儿的修改和后来的神经发育；以及(3)确定照顾者痛苦对 VPT婴儿的神经发育。这符合NICHD 2020战略计划的科学优先事项--减少 通过提高对神经发育障碍起源的理解来提高神经发育障碍的发生率 发展进程，并确定潜在目标和最佳干预时机。培训计划 包括实现PI成为独立临床科学家的目标所必需的几个组成部分， 研究神经发育障碍的早期生命危险因素和发病机制。具体地说， 拟议的培训旨在通过在表观遗传分析中增加培训来增强PI的分子遗传学专业知识 通过与专家导师的密集研讨会和实验室经验，并扩大PI的数量 专业知识，包括复杂的纵向分析。新生儿生理学的新教育与新培训 Stress将为PI提供独特的专业知识，这将导致新的调查途径。最后，PI将 发展专业发展技能，这将是成功成为终身教职助理教授和 独立的临床科学家。爱荷华大学的学术环境非常适合提议的 研究和培训。拥有先进的定量方法、表观遗传学和 新生儿生理学专家愿意为PI提供专家指导。新生儿行为学部 每年都有众多关于早产的研究，并拥有基础设施，包括一支优秀的团队 临床研究护士和高危婴儿随访诊所，以支持拟议的研究。爱荷华州 人类遗传学研究所为研究人员提供最先进的高通量基因分析设备 并支持专注于人类遗传学的研究。众多机构组织提供各种不同的 作为一名独立的临床科学家，有机会培养成功所需的技能。

PROJECT SUMMARY/ABSTRACT Preterm birth affects 1 in 10 infants born in the United States, resulting in significant morbidity and economic cost. Children who are born very preterm (VPT; gestational age<32 weeks) have increased risk for impaired neurodevelopment. VPT infants experience increased physiologic stress while their caregivers experience increased psychological distress—both are associated with impaired neurodevelopment. Epigenetic modifications are proposed as a possible mechanism linking physiologic stress and neurodevelopment in VPT infants. The main objective of the proposed research is to identify the mechanisms by which neonatal physiologic stress induces epigenetic modifications that contribute to impaired neurodevelopment, as well as how caregiver distress moderates the relationship between longitudinal neonatal physiologic stress and neurodevelopmental outcomes. Specifically, the proposed research aims to (1) create and validate novel indices of neonatal physiologic stress in VPT infants; (2) identify the effects of neonatal physiologic stress on epigenetic modifications and later neurodevelopment in VPT infants; and (3) determine the effects of caregiver distress on neurodevelopment in VPT infants. This aligns with the NICHD Strategic Plan 2020 scientific priority—to reduce the incidence of neurodevelopmental disorders by improving the understanding of their origins in the developmental process and identifying potential targets and optimal timing for intervention. The training plan includes several components necessary to reach the PI’s goal of becoming an independent clinical scientist, studying early life risk factors and etiological mechanisms in neurodevelopmental disorders. Specifically, the proposed training aims to enhance the PI’s molecular genetic expertise by adding training in epigenetic analyses via intensive workshops and laboratory experiences with an expert mentor and to expand the PI’s quantitative expertise to include complex longitudinal analyses. The new education and training on neonatal physiological stress will provide the PI with unique expertise that will lead to new avenues of investigation. Finally, the PI will develop professional development skills that will be critical for success as a tenure track assistant professor and independent clinical scientist. The academic environment at the University of Iowa is well-suited for the proposed research and training. Faculty members with expertise in advanced quantitative methods, epigenetics, and neonatal physiology are willing to provide expert mentorship to the PI. The Division of Neonatology conducts numerous research studies on preterm birth each year and has the infrastructure, including an outstanding team of clinical research nurses and a high-risk infant follow-up clinic, to support the proposed research. The Iowa Institute of Human Genetics provides researchers with a state-of-the-art, high-throughput genetic analysis facility and supports research focused on human genetics. Numerous institutional organizations provide a variety of opportunities to develop the skills necessary for success as an independent clinical scientist.