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

人类胎盘发育迟缓和生长调节基因的纵向研究

基本信息

批准号：
8904045
负责人：
Beverly Ilse Strassmann
金额：
$ 22.68万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-05 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8904045
关键词：
3 year old 5 year old 7 year old Adult Adverse effects Affect Africa African Age Alleles Area Basic Science Birth Child Childhood Chronic Cohort Studies Collection Communicable Diseases Conflict (Psychology)Country Data Development Epigenetic Process Etiology Fathers Fetal Growth Fetus First Births Future Generations Genes Genome Genomic Imprinting Germ Lines Glucose Growth Growth and Development function Health Height Hospitals Human Hypertension IGF2 gene Income Individual Intervention Laboratories Length Life Life Experience Light Lipids Longitudinal Studies Mali Malnutrition Measures Metabolic Michigan Mothers Organ Size Ovum Donor PHLDA2 gene Parents Pathology Placenta Play Policies Population Positioning Attribute Prevalence Property Protocols documentation Puberty Quality of life Relative (related person)Repression Research Resource Allocation Resources Risk Role Rural Site Testing Time Universities Variant Wife cognitive function deep sequencing derepression early childhood epigenome expectation experience girls global health imprint in utero infancy innovation interest meetings next generation offspring prevent prospective teenage mother transmission process

项目摘要

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.

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中很常见，其中三分之一的5岁以下儿童受到影响1。非洲的发病率最高，并且是近年来发育迟缓率最小的大陆2。小母亲倾向于生育小婴儿3，但是基于这种相关性的表观遗传机制知之甚少。 [200]母亲对胎盘中的30个印迹基因的这项探索性研究将检验以下假设：遗传印迹在发育迟缓的代际传播中起作用。拟议的研究具有创新性，因为它利用了一项对非洲农村人口的前瞻性队列研究，在该研究中，从婴儿期到儿童期到她的第一个出生，我们追随600名女孩（F1代）。这些受试者的父母（F0）和后代（F2）也收集了数据。我们处于一个独特的位置，将这些纵向数据结合在一起，跨越了3代，并分析了胎盘基因的等位基因特异性表达。 [根据冲突假设4，在父亲等位基因上抑制了生长抑制基因，并且促进生长基因在母亲等位基因上受到抑制。个人之间的烙印程度各不相同，我们假设这种正常变异是从一代传播发育迟缓的机制。 AIM 1将找出孕产妇发育迟缓是否与促进IGF2等生长基因的胎盘印迹较高有关。 AIM 2评估了发育迟缓的关键窗口，以及发育迟缓和追赶增长之间的相互作用。 AIM 3将确定胎盘中促进生长基因的抑制是否增加会导致后代发育迟缓，如出生时和一个月时的仰卧长度来衡量。]胎盘收集将由我们的马里合作者进行，包括两个中妻和一名助理，包括居住在Mali Centraliagara in Centraliagara in Centraliagara in Central Mali的医院助理。该地点是和平的，距离基尔加尔（Kidal）是政治紧张局势的500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个由密歇根大学的PI实验室进行了分析。由于发育迟缓会导致从不良的认知功能到代谢综合征5的广泛健康问题，因此了解它是如何传播到下一代非常重要的。拟议的研究是基础科学，最终发现干预措施和政策，这些干预措施和政策可以防止发育迟缓及其对生活质量的不利影响。