Neural Regulation of Prepartum Cervical Ripening

产前宫颈成熟的神经调节

基本信息

  • 批准号:
    8187156
  • 负责人:
  • 金额:
    $ 27.87万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-02-10 至 2016-04-30
  • 项目状态:
    已结题

项目摘要

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. 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.
描述(由申请人提供):与分娩过程有关的并发症是产科、母婴医学以及新生儿和儿科学领域最大的挑战。早产是一个日益严重的短期和长期问题,而分娩进展缓慢通常与宫颈不成熟有关,并导致美国剖腹产率惊人地上升,超过所有分娩的30%。无论是早或晚,导致分娩和分娩的根本问题是什么是宫颈成熟的机制?前一个资助期的研究结果为宫颈重塑建立了可复制的形态终点。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这一新概念提供了支持。盆腔和迷走神经被发现调节巨噬细胞的迁移,与宫颈成熟和横断术延迟出生有关。此外,孕激素还通过宫颈中的免疫细胞调节驻留。本提案整合了这些发现,以进一步了解宫颈成熟过程中炎症过程的神经控制。这一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。最近,随着激光扫描共聚焦显微镜系统和7色MACSQuant流式细胞仪的问世,研究宫颈免疫细胞特定功能活动的技术取得了进展。建立了新的方法学能力来计数表达啮齿动物宫颈活动的特定细胞标记的免疫细胞。这些研究的实验模型和终点是精心选择的,因为它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准确时间获得宫颈的能力,以及高度特异的试剂的可用性。该提案的两个主要具体目标是确定副交感神经调节产前宫颈重塑的机制,以及确定黄体酮退出在成熟过程中的作用。免疫细胞迁移的神经控制和与胶原蛋白溶解相关的活动是可望的。孕酮受体异构体或基因通路的局部产前改变是否由孕酮的全身性变化驱动,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、氧化应激和黄体酮停用。这些指标可作为早熟或晚熟的新诊断指标。此外,研究结果将支持一个更广泛的视角,即创新地使用神经调节剂或炎症调节剂来阻止或逆转早产或早产,或者在出现延迟分娩的并发症的情况下,使用促进成熟和分娩的干预措施。 公共卫生相关性:早期或复杂的延迟分娩造成的重大健康后果。了解神经支配和孕激素在宫颈成熟机制中的作用是免疫细胞激活和孕酮撤除以重塑宫颈细胞外基质的研究重点。这些创新的努力为开发新的诊断能力和治疗方法提供了潜力,以评估宫颈成熟并阻止降低早产风险的促炎过程。

项目成果

期刊论文数量(0)
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STEVEN M YELLON其他文献

STEVEN M YELLON的其他文献

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{{ truncateString('STEVEN M YELLON', 18)}}的其他基金

NEURAL REGULATION OF PREPARTUM CERVICAL RIPENING
产前宫颈成熟的神经调节
  • 批准号:
    7933164
  • 财政年份:
    2009
  • 资助金额:
    $ 27.87万
  • 项目类别:
NEURAL REGULATION OF PREPARTUM CERVICAL RIPENING
产前宫颈成熟的神经调节
  • 批准号:
    7558497
  • 财政年份:
    2007
  • 资助金额:
    $ 27.87万
  • 项目类别:
Neural Regulation of Prepartum Cervical Ripening
产前宫颈成熟的神经调节
  • 批准号:
    8303195
  • 财政年份:
    2007
  • 资助金额:
    $ 27.87万
  • 项目类别:
NEURAL REGULATION OF PREPARTUM CERVICAL RIPENING
产前宫颈成熟的神经调节
  • 批准号:
    7758823
  • 财政年份:
    2007
  • 资助金额:
    $ 27.87万
  • 项目类别:
NEURAL REGULATION OF PREPARTUM CERVICAL RIPENING
产前宫颈成熟的神经调节
  • 批准号:
    7184496
  • 财政年份:
    2007
  • 资助金额:
    $ 27.87万
  • 项目类别:
NEURAL REGULATION OF PREPARTUM CERVICAL RIPENING
产前宫颈成熟的神经调节
  • 批准号:
    7354068
  • 财政年份:
    2007
  • 资助金额:
    $ 27.87万
  • 项目类别:
Neural Regulation of Prepartum Cervical Ripening
产前宫颈成熟的神经调节
  • 批准号:
    8458544
  • 财政年份:
    2007
  • 资助金额:
    $ 27.87万
  • 项目类别:
NEUROENDOCRINE/IMMUNE INTERACTIONS: ROLE OF MELATONIN
神经内分泌/免疫相互作用:褪黑激素的作用
  • 批准号:
    6041782
  • 财政年份:
    2000
  • 资助金额:
    $ 27.87万
  • 项目类别:
NEUROENDOCRINE/IMMUNE INTERACTIONS: ROLE OF MELATONIN
神经内分泌/免疫相互作用:褪黑激素的作用
  • 批准号:
    6330628
  • 财政年份:
    2000
  • 资助金额:
    $ 27.87万
  • 项目类别:
NEUROENDOCRINE/IMMUNE INTERACTIONS: ROLE OF MELATONIN
神经内分泌/免疫相互作用:褪黑激素的作用
  • 批准号:
    6477181
  • 财政年份:
    2000
  • 资助金额:
    $ 27.87万
  • 项目类别:

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