Neural Regulation of Prepartum Cervical Ripening

描述（由申请人提供）：与分娩过程相关的并发症是产科、母胎医学以及新生儿和儿科领域面临的最重大挑战。早产是一个不断升级的直接和长期问题，而分娩进展失败，通常与子宫颈不完全成熟有关，并导致美国所有分娩中超过30%的剖腹产率惊人地增加。无论是早期还是晚期，导致分娩和分娩的基本问题是子宫颈成熟的机制是什么？上一个资助期的研究结果为重塑宫颈建立了可复制的形态学终点。神经解剖学和显微图像分析的方法提供了支持的新概念，中枢副交感神经系统的神经支配是至关重要的正常的出生时间。盆腔和迷走神经被发现调节巨噬细胞移民与成熟的子宫颈和横切延迟出生。此外，促孕剂还调节宫颈免疫细胞的驻留。目前的建议整合这些发现，采取下一步了解神经支配控制宫颈成熟的炎症过程。这种更新的主要目的是确定神经支配是否调节孕激素受体介导的炎症过程，使宫颈成熟作为分娩最终共同机制的重要早期部分。随着最近获得的激光扫描共聚焦显微镜系统和7色MACSQuant流式细胞仪，开发了研究宫颈免疫细胞特异性功能活动的技术进展。建立了新的方法能力，以计数啮齿动物宫颈中表达特定细胞活动标志物的免疫细胞。这些研究的实验模型和终点是精心选择的，因为与啮齿动物模型和女性的成熟过程相关，以及在相对于出生时间的精确时间获得宫颈的能力和高度特异性试剂的可用性。该提案的两个主要具体目标是确定副交感神经调节子宫颈重塑的机制，并确定孕激素戒断在成熟过程中的作用。免疫细胞迁移的神经控制和与胶原溶解相关的活动是预期的。孕激素受体亚型或基因通路的局部突变是否由孕激素的系统性变化驱动将是研究的重点。预期结果将提高对跨物种宫颈成熟的共同机制的理解，该机制涉及神经信号、促炎过程、氧化应激和孕酮戒断。这些指标可作为新的诊断标记物的早期或延迟开始成熟。此外，研究结果将支持神经调节剂或炎症调节剂的创新使用，以阻止或逆转早产宫颈成熟和早产，或延迟分娩的并发症，促进成熟和分娩的干预措施的更广泛的视角。

DESCRIPTION (provided by applicant): 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.