NEURAL REGULATION OF PREPARTUM CERVICAL RIPENING

描述（由申请人提供）：细胞和生物化学的变化，定义成熟的子宫颈准备早在出生前发生。最近的研究表明，成熟过程与炎症有关；白细胞的迁移和激活与发现在出生前一天，小鼠子宫颈的局部神经支配和中央连接的可塑性增加相一致。基于这些发现，本研究的主要目的是验证神经信号对子宫颈重构机制至关重要的假设。研究计划采用系统的方法，重点关注盆腔、下腹和迷走神经通路的作用，它们的感觉和自主神经投射，以及孕酮在妊娠结束时宫颈炎症和重塑中的作用。在小鼠和大鼠中建立了神经纤维密度的估计方法，并追踪了从子宫颈到大脑的神经投射。尽管已报道了与未怀孕子宫颈的中枢连接，但确定妊娠结束时产生一氧化氮纤维和神经肽能纤维增加的确切途径是本提案的主要目标。将采用三种方法来了解神经支配对妊娠宫颈重塑的重要性：在Specific Aim 1中，将从组织学上评估手术去神经支配的效果，以确定每种途径在出生前增强进入妊娠宫颈的神经纤维密度的相对贡献。去神经支配的特定感觉传入，而不是其他的神经投射，被认为是破坏宫颈成熟。第二项研究将探索通过化学神经切除术消除的特定神经递质阻碍子宫颈重塑的可能性。在特异性目标2中，逆行神经束示踪剂将用于研究子宫颈、脊髓和大脑之间的初级和多突触神经连接。在最后一个具体的目的，神经投射及其活动的调节子宫颈足月前提出依赖于黄体酮的功能撤回。黄体酮的营养作用减少，可诱导局部神经增生，中枢可塑性，并启动炎症级联反应，使子宫颈成熟，为分娩做准备。宫颈神经源性炎症的相关时间进程评估可以预测妊娠的进展，并可以证明对准确预测足月分娩或病理重塑时早产的指示有用。因此，我们的研究结果有望为成熟机制和新的神经免疫治疗方法提供新的见解，以促进子宫颈扩张或抑制早产的发生率。

DESCRIPTION (provided by applicant): The cellular and biochemical changes that define ripening of the prepartum cervix occur well before birth. Recent findings indicate that the ripening process is associated with inflammation; immigration and activation of leukocytes coincide with the discovery of an increased local innervation and plasticity of central connections to the murine cervix by the day before birth. Based upon these findings, the main objective of this proposal is to test the hypothesis that neural signals are essential to the mechanism for remodeling the cervix in preparation for birth. A systematic approach is taken in the Research Plan to focus on the contribution of pelvic, hypogastric, and vagus pathways, their sensory and autonomic projections, as well as the role of progesterone withdrawal on inflammation and remodeling in the cervix at the conclusion of pregnancy. Methods were developed to estimate nerve fiber density and to trace neural projections from the cervix to the brain in mice and rats. Although central connections to the nonpregnant cervix have been reported, determination of precisely which pathways are responsible for the increase in nitric oxide-producing fibers and neuropeptidergic fibers at the conclusion of pregnancy is the major objective of this proposal. Three approaches will be taken to understand the importance of innervation for remodeling the pregnant cervix: In Specific Aim 1, effects of surgical denervation will be assessed histologically to determine the relative contribution of each pathway to enhance the density of nerve fibers into the pregnant cervix before birth. Denervation of specific sensory afferents, but not other neural projections, is proposed to disrupt cervical ripening. A second study will explore the possibility that specific neurotransmitters, as eliminated by chemical neurectomy, block remodeling of cervix. In Specific Aim 2, retrograde neural tract tracers will be used to study the primary and multisynaptic neural connections between the cervix, spinal cord, and brain. In the last specific aim, regulation of neural projections and their activity in the cervix before term is proposed to depend upon functional withdrawal of progesterone. The reduced trophic action of progesterone is proposed to induce local neural proliferation, central plasticity, and initiation of the inflammatory cascade that ripens the cervix in preparation for birth. Relevant assessments of the time course for neurogenic inflammation in the cervix may foretell the progress of pregnancy and could prove useful to accurately predict when birth will occur at term or, with pathological remodeling, be indicative of preterm delivery. Thus, our findings are expected to provide new insights about the mechanism of ripening and novel neuroimmune therapeutic approaches to either promote dilation of the cervix or inhibit the incidence of preterm birth.