Neural Regulation of Prepartum Cervical Ripening

产前宫颈成熟的神经调节

• 批准号: 8458544
• 负责人: STEVEN M YELLON
• 金额: $ 26.95万
• 依托单位: LOMA LINDA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-10 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458544
• 关键词: Address; Biochemical; Biomechanics; Birth; Brightfield Microscopy; Cells; Cervical; Cervical Ripening; Cervix Uteri; Cesarean section; Chronology; Color; Development; Discipline of obstetrics; Experimental Models; Extracellular Matrix; Failure; Flow Cytometry; Fluorescence Microscopy; Funding; Gatekeeping; Gene Expression; Genes; Goals; Grant; Health; Image Analysis; Immigration; Immune; Immune Cell Activation; Immunohistochemistry; Inflammation; Inflammatory; Intervention; Lasers; Lead; Mediating; Microscope; Microscopic; Molecular; Neonatology; Nerve; Neuroimmunomodulation; Neuromodulator; Neurotransmitters; Outcome; Oxidative Stress; Parasympathetic Nervous System; Pathway interactions; Pediatrics; Pelvis; Phase Transition; Premature Birth; Premature Labor; Preparation; Process; Progesterone; Progesterone Receptors; Progestins; Protein Isoforms; Publishing; Rattus; Reagent; Regulation; Relative (related person); Residencies; Risk; Rodent; Rodent Model; Role; Scanning; Signal Transduction; System; Therapeutic; Therapeutic Intervention; Time; Vagus nerve structure; Withdrawal; Woman; activity marker; cell motility; falls; fetal medicine; improved; in utero; indexing; innovation; insight; macrophage; nerve supply; neuroregulation; novel; novel diagnostics; novel therapeutic intervention; peer; premature; pup; relating to nervous system; tool; trafficking

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.

描述（由申请人提供）：与分娩过程相关的并发症代表了产科、母胎医学以及新生儿学和儿科领域最重大的挑战。早产是一个不断升级的即时和长期问题，而分娩进展失败，通常与宫颈不完全成熟有关，并导致美国剖宫产率的惊人增长，超过30%的分娩。无论是早还是晚，导致分娩和分娩的关键问题是子宫颈成熟的机制是什么？先前资助期的研究结果为重塑子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方法为中枢副交感神经系统的神经支配对正常出生时间至关重要的新概念提供了支持。发现盆腔和迷走神经调节巨噬细胞迁移，与子宫颈成熟和横切延迟分娩有关。此外，孕激素也调节免疫细胞在子宫颈的驻留。目前的建议整合了这些发现，采取下一步了解神经支配的炎症过程在宫颈成熟。这项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，使子宫颈成熟，作为最终分娩共同机制的重要早期部分。随着激光扫描共聚焦显微镜系统和7色MACSQuant流式细胞仪的出现，研究子宫颈免疫细胞特异性功能活动的技术取得了进展。建立了新的方法能力来枚举在啮齿动物子宫颈中表达特定细胞标志物的免疫细胞。这些研究的实验模型和终点都是精心选择的，因为它们与啮齿动物模型和女性的成熟过程有关，并且能够在相对于出生时间的精确时间获得服务，并且可以获得高度特异性的试剂。该提案的两个主要具体目的是确定副交感神经调节子宫颈重构的机制，以及确定黄体酮在成熟过程中的作用。预计免疫细胞迁移和胶原溶解相关活动的神经控制。孕酮受体异构体或基因通路的局部预备转移是否由孕酮的系统性变化驱动将是一个特别的研究重点。预期的结果将提高对跨物种子宫颈成熟的共同机制的理解，包括神经信号、促炎过程、氧化应激和黄体酮戒断。这些指标可以作为早熟或延迟成熟的新诊断指标。此外，研究结果将为神经调节剂或炎症调节剂的创新应用提供更广泛的视角，以阻止或逆转宫颈过早成熟和早产，或者在并发症延迟分娩的情况下，促进成熟和分娩的干预措施。