A longitudinal study of stunting and growth modulating genes in human placentas

描述(由申请人提供)：发育迟缓是一个全球健康问题，在低收入和中等收入国家很常见，那里有三分之一的5岁以下儿童受到影响。非洲的发育迟缓率最高，也是近年来发育迟缓患病率改善最少的大陆。体型较小的母亲往往会生下较小的婴儿，但这种相关性背后的表观遗传机制却鲜为人知。这项对来自[200]名母亲的胎盘中30个印记基因的探索性研究将检验基因印记在发育迟缓的代际传播中发挥作用的假设。这项拟议的研究具有创新性，因为它利用了一项针对非洲农村人口的前瞻性队列研究，在该研究中，我们跟踪了600名女孩(F1一代)从婴儿期到儿童期，直到她们的第一个孩子。关于这些受试者的父母(F0)和子女(F2)的数据也在收集中。我们处于一个独特的位置，可以将这些跨越3代的纵向数据与胎盘基因的等位基因特异性表达分析结合起来。[根据冲突假说4，生长抑制基因在父亲的等位基因上受到抑制，而生长促进基因在母亲的等位基因上受到抑制。印记的程度因个体而异，我们假设这种正常的变异是发育迟缓从一代传给下一代的机制。目标1将找出母亲发育迟缓是否与胎盘中IGF2等促进生长基因的印记水平较高有关。目标2评估了发育迟缓的关键窗口，以及发育迟缓和追赶生长之间的相互作用。目标3将找出胎盘中促进生长基因的抑制增加是否会导致后代发育迟缓，以出生时和一个月大时的仰卧长度衡量。]胎盘采集将由我们的马里合作者进行，其中包括两名助产士和一名医院助理，他们永久居住在研究地点[马里中部班加加拉地区]。这个地方很和平，距离政治紧张的基达尔500多英里。研究小组对所有方案进行了现场测试，并收集了22个胎盘，其中5个已由密歇根大学的PI实验室进行了分析。]我们将使用聚合酶链式反应和深度测序相结合的方法来高精度地测量印迹丢失。由于发育迟缓会导致一系列的健康问题，从认知功能低下到代谢综合征，了解它是如何传染给下一代的很重要。拟议的研究是一项基础科学，对于最终发现预防发育迟缓及其对生活质量的不利影响的干预措施和政策是必要的。

DESCRIPTION (provided by applicant): Stunting is a global health problem that is common in low and middle-income countries where one third of children under 5 years of age are affected1. Africa has the highest rates of stunting and is the continent that has shown the least improvement in the prevalence of stunting in recent years2. Small mothers tend to give birth to small babies3, but the epigenetic mechanisms that underlie this correlation are poorly understood. This exploratory study of 30 imprinted genes in placentas from [200] mothers will test the hypothesis that genetic imprinting plays a role in the inter-generational transmission of stunting. The proposed study is innovative because it takes advantage of a prospective cohort study of a rural African population in which we are following 600 girls (F1 generation) from infancy, through childhood, to their first birth. Data are also being gathered on the parents (F0) and offspring (F2) of these subjects. We are in a unique position to combine these longitudinal data, spanning 3 generations, with the analysis of allele-specific expression of placental genes. [According to the conflict hypothesis4, growth inhibiting genes are repressed on the paternal alleles and growth promoting genes are repressed on the maternal alleles. The degree of imprinting varies between individuals and we hypothesize that this normal variation is the mechanism by which stunting is transmitted from one generation to the next. Aim 1 will find out if maternal stunting is associated with higher levels of placental imprinting of growth promoting genes such as IGF2. Aim 2 assesses the critical windows at which stunting matters, and the interaction between stunting and catch up growth. Aim 3 will find out if increased repression of growth promoting genes in the placenta leads to offspring stunting, as measured by supine length at birth and at age one month.] The placental collections will be carried out by our Malian collaborators, including two mid-wives and a hospital assistant who reside permanently at the study site [in the District of Bandiagara in central Mali. This site is peaceful and more than 500 miles from Kidal, an area of political tension. The research team has field-tested all the protocols and collected 22 placentas, 5 of which have been analyzed by the PI's laboratory at the University of Michigan.] We will use a combination of PCR and deep sequencing to measure loss of imprinting with high accuracy. As stunting leads to a wide range of health problems from poor cognitive function to metabolic syndrome5, it is important to understand how it is transmitted to the next generation. The proposed study is basic science that is necessary for the eventual discovery of interventions and policies that prevent stunting and its adverse effects on the quality of life.