EMA Assessment of Biobehavioral Processes in Human Pregnancy

描述（由申请人提供）：本提案的目标是扩展我们正在进行的研究的范围，以测试关于宫内生活期间母体-胎盘-胎儿应激生物学对人类新生儿和婴儿端粒生物学系统的影响的特定假设。阐明宫内环境对随后的健康和疾病风险结果（胎儿/发育规划）的影响的生物学机制是一个积极关注和深入研究的领域。我们提出的假设，端粒生物学可能是一个重要的和新的机制，观察到的影响不同的次优宫内暴露对随后的健康和疾病风险表型的利益。我们建议关注两个关键的端粒生物学相关结果-出生时和12个月龄时的白细胞端粒长度，以及出生时促分裂原刺激的白细胞端粒酶表达，以及人类妊娠中主要生物学途径的影响-压力相关的母体-胎盘-胎儿（MPF）内分泌，免疫/炎症和氧化状态-可能介导各种次优条件对发育中的胎儿的影响。我们将在一个代表性的、基于人群的队列中进行一项前瞻性、纵向、随访研究，该队列包括N=120名新生儿，从出生（T1）到出生后早期生长阶段直至12个月龄（T2）。我们的提案的独特优势在于我们的“母”项目（RO 1 HD-060628，RO 1 HD-065825）中提供了一组新生儿和婴儿，这些新生儿和婴儿在宫内和产后生活过程中采用本研究所需的措施进行了广泛表征。另一个值得注意的特点包括我们的跨学科研究团队，他们在母亲-胎盘-胎儿应激生物学（Pathik Wadhwa，Sonja Entringer），端粒生物学（Elizabeth Blackburn，Elissa Epel，Jue Lin），免疫学（Edward纳尔逊）和产科/妇产科（Deborah Wing，Hyaglivan Simhan）方面具有合作记录和广泛的出版专业知识。我们将讨论以下具体目的：1）检验以下假设：暴露于升高的宫内生物应激可预测a）新生儿白细胞端粒长度（LTL）和B）从出生到12个月龄LTL的变化。2)探讨宫内生物应激对新生儿白细胞端粒酶活性的预测作用。3)在确定哪些措施的宫内应激生物学（在妊娠的特定时间点）预测新生儿和婴儿的LTL和端粒酶活性，我们将解决探索性的问题，其决定因素使用现有的综合数据收集在正在进行的“父母”项目。本研究的意义和影响来自于更好地理解改变随后健康和疾病风险结果的风险或脆弱性的基本过程（机制）的重要性。这项研究将收集新的数据（新生儿和婴儿端粒生物学的系列措施），并解决为转化研究奠定基础的假设。我们认为，这项拟议的研究代表了母项目科学范围的适当扩大。

DESCRIPTION (provided by applicant): The goal of this proposal is to extend the scope of our on-going studies to test specific hypotheses regarding the effects of maternal-placental-fetal stress biology during intrauterine life on the human newborn and infant telomere biology system. The elucidation of biological mechanisms underlying the effects of the intrauterine environment on subsequent health and disease risk outcomes (fetal/developmental programming) is an area of active interest and intense investigation. We advance the hypothesis that telomere biology may represent an important and novel mechanism underlying the observed effects of disparate suboptimal intrauterine exposures on subsequent health and disease risk phenotypes of interest. We propose to focus on two key telomere biology-related outcomes - leukocyte telomere length at birth and at 12 months age, and mitogen-stimulated leukocyte telomerase expression at birth, and on the effects of a major biological pathway in human gestation - stress-related maternal-placental-fetal (MPF) endocrine, immune/inflammatory and oxidative state - that may mediate the effects of a diverse set of suboptimal conditions on the developing fetus. We will conduct a prospective, longitudinal, follow-up study in a representative, population-based cohort of N=120 newborns from birth (T1) and over the early postnatal growth phase until 12 months age (T2). A unique strength of our proposal is the availability in our "parent" projects (RO1 HD-060628, RO1 HD-065825) of a cohort of newborns and infants who are extensively characterized over the course of intrauterine and postnatal life with the measures required in the present study. Another notable feature includes our trans-disciplinary team of investigators with a collaboration record and extensive, published expertise in maternal-placental-fetal stress biology (Pathik Wadhwa, Sonja Entringer), telomere biology (Elizabeth Blackburn, Elissa Epel, Jue Lin), immunology (Edward Nelson), and obstetrics/neonatology (Deborah Wing, Hyagriv Simhan). We will address the following Specific Aims: 1) To test the hypothesis that exposure to elevated intrauterine biological stress predicts a) newborn leukocyte telomere length (LTL) and b) change in LTL from birth till 12 months age. 2) To test the hypothesis that exposure to elevated intrauterine biological stress predicts newborn leukocyte telomerase activity. 3) After identifying which measures of intrauterine stress biology (and at which specific time points in gestation) predict newborn and infant LTL and telomerase activity, we will address exploratory questions of their determinants using the available comprehensive data collected in the on-going "parent" projects. The significance and impact of this study derives from the importance of achieving at a better understanding of underlying processes (mechanisms) that alter risk or vulnerability for subsequent health and disease risk outcomes. This study will collect novel data (serial measures of newborn and infant telomere biology) and address hypotheses that set the stage for translational research. We submit that this proposed study represents an appropriate expansion of the scientific scope of the parent project.