Complications related to the process of parturition represent the most significant challenges to the field of Obstetrics, Maternal-Fetal Medicine, as well as for Neonatology, and Pediatrics. Preterm birth is an escalating immediate and long-term problem while failure of labor to progress, often related to incomplete ripening of the cervix, and contributes to an alarming increase in the Cesarean section rate of more than 30% of all deliveries in the USA. Whether early or late, the essential question that leading up to labor and delivery is what is the mechanism for ripening the cervix? Findings from the previous funding period established replicable morphological endpoints for remodeling the cervix. Neuroanatomical and microscopic image analyses approaches provided support for the novel concept that innervation by the central parasympathetic nervous system is critical for the normal timing of birth. The pelvic and vagus nerves were found to regulate macrophages immigration in association with ripening of the cervix and transections delayed birth. Moreover, progestational agents also regulated residency by immune cells in the cervix. The present proposal integrates these discoveries to take next steps for understanding innervation control of inflammatory processes in cervical ripening. The principal objective of this renewal is to determine whether innervation regulates a progesterone receptor-mediated inflammatory process that ripens the cervix as an essential early part of the final common mechanism for parturition. Technological advances to investigate specific functional activities by immune cell in cervix were developed with the recent acquisition of a laser scanning Confocal microscope system and a 7-color MACSQuant flow cytometer. New methodological capabilities were established to enumerate immune cellsthat express specific cellular markers of activities in the rodent cervix. Experimental models and endpoints for these studies were carefully chosen because of relevance to the ripening processes in rodent models and for women, as well as ability to acquire cervices at precise times relative to timing of birth and availability of highly specific reagents. The two major specific aims of the proposal are to determine the mechanism for parasympathetic regulation of remodeling in the prepartum cervix and to determine the role of progesterone withdrawal in the ripening process. Neural control of immune cell migration and activities related to collagenolysis are expected. Whether a local prepartum shift in progesterone receptor isoforms or gene pathways is driven by systemic changes in progesterone will be a particular focus of study. Expected outcomes will improve understanding of a common mechanism for ripening of the cervix across species that involved neural signals, proinflammatory processes, oxidative stress, and progesterone withdrawal. These indices may serve as novel diagnostic markers for early or delayed onset of ripening. Moreover, findings will support a broader perspective for the innovative use of neuromodulators or inflammatory regulators to arrest or reverse preterm cervical ripening and premature labor or, with complications that delay birth, interventions that promote ripening and parturition.

Public Health Relevance

Major Health consequences result from early or complicated delayed birth. Understanding the role of innervation and progestational agents in the mechanism for ripening the cervix is the focus of studies on activation of immune cells and progesterone withdrawal for remodeling the extracellular matrix in the cervix. These innovative efforts provide the potential for development of novel diagnostic capabilities and therapeutic approaches to assess cervical ripening and block proinflammatory processes that reduce risks for preterm birth.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
Program Officer
Signore, Caroline
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Loma Linda University
Other Basic Sciences
Schools of Medicine
Loma Linda
United States
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Yellon, Steven M (2017) Contributions to the dynamics of cervix remodeling prior to term and preterm birth. Biol Reprod 96:13-23
Dubicke, Aurelija; Ekman-Ordeberg, Gunvor; Mazurek, Patricia et al. (2016) Density of Stromal Cells and Macrophages Associated With Collagen Remodeling in the Human Cervix in Preterm and Term Birth. Reprod Sci 23:595-603
Kirby, Michael A; Heuerman, Anne C; Custer, Melisa et al. (2016) Progesterone Receptor-Mediated Actions Regulate Remodeling of the Cervix in Preparation for Preterm Parturition. Reprod Sci 23:1473-1483
Dobyns, Abigail E; Goyal, Ravi; Carpenter, Lauren Grisham et al. (2015) Macrophage gene expression associated with remodeling of the prepartum rat cervix: microarray and pathway analyses. PLoS One 10:e0119782
Yellon, Steven M; Dobyns, Abigail E; Beck, Hailey L et al. (2013) Loss of progesterone receptor-mediated actions induce preterm cellular and structural remodeling of the cervix and premature birth. PLoS One 8:e81340
Nold, Christopher; Maubert, Monique; Anton, Lauren et al. (2013) Prevention of preterm birth by progestational agents: what are the molecular mechanisms? Am J Obstet Gynecol 208:223.e1-7
Payne, Kimberly J; Clyde, Lindsey A; Weldon, Abby J et al. (2012) Residency and activation of myeloid cells during remodeling of the prepartum murine cervix. Biol Reprod 87:106
Yellon, Steven M; Oshiro, Bryan T; Chhaya, Tejas Y et al. (2011) Remodeling of the cervix and parturition in mice lacking the progesterone receptor B isoform. Biol Reprod 85:498-502
Clyde, Lindsey A; Lechuga, Thomas J; Ebner, Charlotte A et al. (2011) Transection of the pelvic or vagus nerve forestalls ripening of the cervix and delays birth in rats. Biol Reprod 84:587-94
Kirby, Michael A; Groves, Mary M; Yellon, Steven M (2010) Retrograde tracing of spinal cord connections to the cervix with pregnancy in mice. Reproduction 139:645-53

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