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

• 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
• 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

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周之前出生，是新生儿死亡的主要原因。 发病率和死亡率。在高收入经济体中，美国的PTB患病率最高， 几乎占所有出生人口的10%。早产儿一生中患严重神经发育的风险增加， 胃肠道和呼吸系统并发症。这导致生活质量下降， 负担此外，PTB还与母亲终身心血管疾病风险增加有关。不 令人惊讶的是，了解PTB的基本机制对于使命来说是非常重要的 的NIH。尽管导致肺结核的机制多种多样，但与肺结核的调节异常有关的一个共同因素是肺结核的发病机制。 母胎界面和PTB是炎症。 遗传组成在PTB易感性中起着重要作用，特别是在对感染或 炎症尽管有现代技术，对PTB遗传结构的研究一直具有挑战性， 很难获得清晰可重复的证据。重要的问题包括不清楚的表型和 混淆社会或环境因素。此外，伦理方面的考虑限制了宫内节育器的使用。 在人类怀孕期间。 尽管胎盘形成、激素调节和免疫反应存在差异，但 支持它们用于描述复杂分子之间的因果关系的共性 与PTB有关的途径。PTB动物模型的另一个优点是能够控制时间和 暴露和环境的特殊性。然而，研究遗传框架的主要方法 到目前为止，潜在的PTB一直是检查在小鼠中操纵候选基因的结果， 株这错过了检查PTB中自然遗传变异的机会。 协作杂交（CC）小鼠遗传资源提供了前所未有的机会， 复杂表型的高分辨率系统遗传学分析，如PTB。我们相信，利用我们的 在小鼠脂多糖（LPS）诱导的PTB检查以及小鼠和人类遗传学方面拥有专业知识， 沿着CC资源代表了研究PTB潜在机制的重要下一步 在小鼠模型中。我们的总体假设是CC菌株将适当地模拟自然遗传变异 与PTB易感性、发病机制和疾病进展相关。我们建议使用R21 i）确定CC中LPS诱导的PTB易感性 菌株，并使用现有的基因组作图数据进行连锁分析。2.确定LPS的影响 使用RNA-seq技术进行曝光。我们相信这些方法将导致遗传位点的识别 预防，导致或加剧PTB，并将成为未来机制研究的坚实基础或新的 这些方法将允许进一步了解如何在妇女中治疗或预防PTB。