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.
