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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD054931-06
Application #
8303195
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Ilekis, John V
Project Start
2007-02-10
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
6
Fiscal Year
2012
Total Cost
$284,006
Indirect Cost
$92,756
Name
Loma Linda University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
009656273
City
Loma Linda
State
CA
Country
United States
Zip Code
92350
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
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
Yellon, Steven M; Grisham, Lauren A; Rambau, Genevieve M et al. (2010) Pregnancy-related changes in connections from the cervix to forebrain and hypothalamus in mice. Reproduction 140:155-64
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
Boyd, Jonathan W; Lechuga, Thomas J; Ebner, Charlotte A et al. (2009) Cervix remodeling and parturition in the rat: lack of a role for hypogastric innervation. Reproduction 137:739-48
Yellon, Steven M; Ebner, Charlotte A; Elovitz, Michal A (2009) Medroxyprogesterone acetate modulates remodeling, immune cell census, and nerve fibers in the cervix of a mouse model for inflammation-induced preterm birth. Reprod Sci 16:257-64
Yellon, Steven M; Burns, Alexandra E; See, Jennifer L et al. (2009) Progesterone withdrawal promotes remodeling processes in the nonpregnant mouse cervix. Biol Reprod 81:1-6