Mechanistic Analyses of the Genetic Variation of Preterm Birth Using the Collaborative Cross Mice

使用协作杂交小鼠对早产遗传变异的机制分析

基本信息

批准号：
10408845
负责人：
ELIZABETH A. BONNEY
金额：
$ 19.12万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-21 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10408845
关键词：
37 weeks gestation Acceleration Address Animal Model Autoimmunity Biological Birth Blood Vessels Candidate Disease Gene Cervical Chronic stress Clinical Communicable Diseases Complex Data Development Diagnosis Disease Progression Economic Burden Economics Elements Environment Environmental Risk Factor Ethics Exploratory/Developmental Grant Exposure to Future Genes Genetic Genetic Markers Genetic Predisposition to Disease Genetic Variation Genetic study Genome Genome Mappings Gestational Age Gram-Negative Bacteria Hour Human Human Genetics Immune Immune response Inbred Strains Mice Income Infant Infection Inflammation Inflammatory Investigation Laboratories Lead Learning Length Link Lipopolysaccharides Maternal-Fetal Exchange Medical Mission Modeling Modernization Molecular Mothers Mus Neonatal Neonatal Mortality Pathogenesis Pathway interactions Phenotype Placenta Placentation Play Population Predisposition Pregnancy Premature Birth Premature Infant Premature Labor Premature Rupture Fetal Membranes Prevalence Prevention Progesterone Proteins Quality of life Quantitative Trait Loci RNA RNA Splicing Race Recombinants Regulation Reproducibility Resolution Resources Risk Role Saline Site Specificity Stimulus Stress Structure Syndrome System Techniques Technology Testing Tissues Transcript Uncertainty United States National Institutes of Health Uterine Contraction Uterus Variant Withdrawal Woman cardiovascular disorder risk endoplasmic reticulum stress epigenetic variation fetal gastrointestinal genetic analysis genetic approach genetic architecture genetic association genetic linkage analysis genetic makeup genetic resource genomic locus hormone regulation hypothalamic-pituitary-adrenal axis implantation improved macrophage microbiome mouse genetics mouse model neonatal morbidity novel strategies pregnant prevent programs reproductive reproductive outcome respiratory response social factors transcriptome sequencing

项目摘要

Preterm birth (PTB), defined as birth prior to 37 weeks of gestation, is the leading cause of neonatal morbidity and mortality. Among high-income economies, prevalence of PTB is highest in the USA, occurring in nearly 10% of all births. Prematurely born infants have a lifetime increased risk for severe neurodevelopmental, gastrointestinal, and respiratory complications. This contributes to reduced quality of life and significant economic burden. Moreover, PTB is also associated with lifelong increased cardiovascular disease risk in the mother. Not surprisingly, understanding the mechanisms underlying PTB is of significant importance to the mission of NIH. Although the mechanisms leading to PTB are varied, a common element linking dysregulation at the maternal-fetal interface and PTB is inflammation. Genetic makeup plays an important role in predisposition to PTB, particularly in response to infection or inflammation. Despite modern techniques, investigation of the genetic architecture of PTB has been challenging, and clear, reproducible evidence has been difficult to achieve. Significant issues include unclear phenotype and confounding social or environmental factors. Moreover, ethical considerations limit access to intrauterine contents during human pregnancy. Although differences in placentation, hormonal regulation, and immune response exist, there are commonalities which support their use to delineate cause and effect relationships amongst complex molecular pathways related to PTB. Another advantage of animal models of PTB is the ability to control timing and specificity of exposures and the environment. However, the primary approach to examine the genetic framework underlying PTB thus far has been to examine the result of manipulating candidate genes in mice of a single strain. This misses the opportunity to examine natural genetic variation in PTB. The Collaborative Cross (CC) mouse genetic resource offers unprecedented opportunities for accurate, high-resolution systems-genetics analyses of complex phenotypes, such as PTB. We believe that leveraging our expertise in the examination of lipopolysaccharide(LPS)-induced PTB in mice and in mouse and human genetics, along with the CC resource represents a significant next step in investigating the mechanisms underlying PTB in a mouse model. Our overall hypothesis is that CC strains will appropriately model the natural genetic variation associated with PTB susceptibility, pathogenesis and disease progression. We propose to use the R21 mechanism to pursue the following Specific Aims: i)To determine the LPS-induced PTB susceptibility in CC strains and perform linkage analysis using existing genome mapping data. ii) Determine the impact of LPS exposure using RNA-seq technology. We believe these approaches will lead to the identification of genetic loci that prevent, lead to or exacerbate PTB and will become a firm basis for future mechanistic studies or new approaches that will permit further understanding of how PTB can be treated or prevented in women.

早产（PTB）定义为妊娠37周之前的出生，是新生儿的主要原因发病率和死亡率。在高收入经济体中，PTB的患病率在美国最高，发生在美国所有分娩的近10％。过早出生的婴儿一生增加了严重神经发育的风险，胃肠道和呼吸并发症。这有助于降低生活质量和大量经济负担。此外，PTB还与母亲的心血管疾病风险增加有关。不是令人惊讶的是，了解PTB的基础机制对任务至关重要 NIH。尽管导致PTB的机制各不相同，但连接失调的常见元素孕产妇界面和PTB是炎症。遗传化妆在PTB易感性中起重要作用，特别是在感染或炎。尽管采用了现代技术，但对PTB遗传结构的调查一直具有挑战性，清楚，可再现的证据很难实现。重大问题包括不清楚的表型和混淆社会或环境因素。此外，道德考虑限制了进入宫内的访问人类怀孕期间的内容。尽管存在胎盘，激素调节和免疫反应的差异，但仍有支持其用于描述复杂分子之间的因果关系和影响关系的共同点与PTB有关的途径。 PTB动物模型的另一个优点是控制时间和暴露和环境的特异性。但是，检查遗传框架的主要方法迄今拉紧。这错过了检查PTB中自然遗传变异的机会。协作十字架（CC）鼠标遗传资源提供了前所未有的机会，以实现准确的，复杂表型（例如PTB）的高分辨率系统基因分析。我们相信利用我们的研究小鼠以及小鼠和人类遗传学中脂多糖（LPS）诱导的PTB的专业知识，与CC资源一起代表了研究PTB基础机制的重要下一步在鼠标模型中。我们的总体假设是，CC菌株将适当地对自然遗传变异进行适当建模与PTB易感性，发病机理和疾病进展相关。我们建议使用R21 追求以下特定目的的机制：i）确定CC中LPS诱导的PTB敏感性使用现有的基因组映射数据来应变并执行链接分析。 ii）确定LPS的影响使用RNA-seq技术接触。我们认为这些方法将导致遗传基因座的识别这可以防止，导致或加剧PTB，并将成为未来机械研究或新的坚定基础可以进一步了解女性可以治疗或预防PTB的方法。