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

点击翻译按钮获取中文摘要

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.