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

早产(PTB)是指在怀孕37周之前出生，是新生儿的主要原因。 发病率和死亡率。在高收入经济体中，肺结核的患病率在美国最高，发生在#年。 几乎占所有新生儿的10%。早产儿患严重神经发育的风险终生增加， 胃肠道和呼吸道并发症。这导致了生活质量的降低和显著的经济 负担。此外，肺结核还与母亲心血管疾病风险的终生增加有关。不 令人惊讶的是，了解肺结核的潜在机制对任务非常重要。 来自美国国立卫生研究院。尽管导致肺结核的机制各不相同，但一个共同的因素与肺组织的调节失调有关 母胎界面和肺结核均为炎症。 基因构成在肺结核的易感性中起着重要作用，特别是在对感染或 发炎。尽管有现代技术，但对肺结核遗传结构的研究一直具有挑战性， 而清晰的、可重复的证据一直很难获得。重要的问题包括表型不清楚和 混杂的社会或环境因素。此外，伦理考虑限制了进入宫内的机会 在人类怀孕期间的内容。 尽管在胎盘、激素调节和免疫反应方面存在差异，但 支持使用它们来描述复杂分子之间的因果关系的共性 与肺结核相关的通路。肺结核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，检查遗传框架的主要方法 到目前为止，潜在的结核病一直是检查在一只小鼠身上操纵候选基因的结果 紧张。这错失了研究肺结核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， 高分辨率系统-复杂表型的遗传学分析，如肺结核。我们相信，利用我们的 在研究脂多糖(LPS)诱导的小鼠肺结核以及小鼠和人类遗传学方面的专业知识， 以及CC资源代表了研究PTB基础机制的重要下一步 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 与肺结核的易感性、发病机制和疾病进展有关。我们建议使用R21 实现以下具体目标的机制：i)确定内毒素诱导的CC对肺结核的敏感性 并利用现有的基因组图谱数据进行连锁分析。二)确定内毒素的影响 使用RNA-SEQ技术进行暴露。我们相信这些方法将导致对遗传基因座的识别 从而预防、导致或加重肺结核，并将成为未来机制研究或新的 将允许进一步了解如何治疗或预防妇女肺结核的方法。

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.