Our understanding of cervical remodeling during pregnancy and labor is incomplete, partly due to the lack of in vivo studies on the biochemical changes that occur in the cervix over the course of pregnancy. Elucidation of the mechanisms for cervical ripening could be used to predict the onset of preterm labor. Until recently, in vivo research methods were too invasive to be used as discovery tools, particularly in women who present with preterm labor. This proposal will use in vivo Raman spectroscopy, an optical technique that is sensitive to collagen content, collagen structure, hydration, lipids, proteins, ad other biomolecules to non-invasively investigate the biochemistry of the cervix throughout pregnancy. Using fiber optic in vivo Raman spectroscopy, we recently found significant differences in Raman spectra in at least four important peaks during the course of pregnancy in mice, including discrete signatures for lipids, collagen, amide bonds, and enriched amino acids (proline, tyrosine). Computational analysis of these spectra yielded predictive algorithms with 94% classification accuracy for stage of pregnancy. Studies performed in 2-hour windows at the end of pregnancy identified spectra predictive for the timing of parturition. This approach provides a detailed real-time biomolecular map of cervical ripening that is currently unavailable by other means. In this proposal, we hypothesize that the different mechanisms of premature cervical ripening have unique Raman spectral signatures that correspond to underlying biochemical and mechanical changes that precede preterm birth, which can be detected in vivo.
Two Specific Aims are proposed: 1) Determine spectral changes in the cervix of mice with normal and abnormal pregnancy and parturition; 2) Identify specific mediators of cervical remodeling by comparing Raman spectra to mechanical and biochemical changes in the ex vivo cervix during normal and abnormal parturition. Raman spectroscopy has primarily been used for detection of disease. Collaboration between our reproductive biology and bioengineering groups will capitalize on our expertise in Raman analysis of cervical tissues to study dynamic changes in cervix composition during pregnancy. Key elements in cervical biochemistry will be identified. In vivo Raman spectroscopy will be combined with biomechanical studies and imaging mass spectrometry, a powerful tool for in situ proteomic analysis, to examine mice with premature or delayed cervical remodeling. Together, these highly innovative approaches will generate in-depth profiles of cervical biology that will translate into novel non-invasive methods to detect impending premature birth in women.
This proposal will use Raman Spectroscopy, a non-invasive, optical scattering technique, to investigate the composition of the cervix throughout pregnancy and provide detailed real-time information on cervical ripening. These studies will identify spectral differences in the cervix during normal and abnormal cervical maturation; optical and biochemical markers will be identified to help monitor pregnancy non-invasively, as the fiber optic probe only requires brief contact with the external surface of the cervix to obtain measurements. Elucidating the mechanisms that initiate cervical ripening will provide a critical step for early detection and treatment of preterm birth, which is the leading cause of infant morbidity and mortality.
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