NEURAL REGULATION OF PREPARTUM CERVICAL RIPENING

描述(由申请人提供)：定义孕期宫颈成熟的细胞和生化变化发生在出生前很久。最近的发现表明，成熟过程与炎症有关；白细胞的迁移和激活与出生前一天发现局部神经和与小鼠宫颈的中枢连接的可塑性增加是一致的。基于这些发现，这项建议的主要目标是测试神经信号对准备分娩时宫颈重塑的机制至关重要的假设。在研究计划中采用了一种系统的方法，着重于盆腔、腹下和迷走神经通路的贡献，它们的感觉和自主神经投射，以及孕酮撤除在妊娠结束时对宫颈炎症和重塑的作用。发展了一种方法来估计神经纤维密度，并追踪从小鼠和大鼠的宫颈到大脑的神经投射。虽然已经报道了与非妊娠宫颈的中枢联系，但确定在妊娠结束时究竟是哪些途径导致了一氧化氮产生纤维和神经肽能纤维的增加是这项建议的主要目标。我们将从三个方面来理解神经支配对妊娠宫颈重塑的重要性：在特定的目标1中，将从组织学角度评估手术去神经的效果，以确定每条途径在胎儿出生前增加进入妊娠宫颈的神经纤维密度的相对贡献。特定感觉神经传入的去神经，而不是其他神经投射，被认为可以扰乱宫颈成熟。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止宫颈重塑的可能性。在具体目标2中，将使用逆行神经束示踪器来研究宫颈、脊髓和脑之间的初级和多突触神经联系。在最后一个特定目标中，在足月前宫颈神经投射及其活动的调节被认为依赖于黄体酮的功能性撤除。孕酮营养作用的减弱被认为是诱导局部神经增殖、中枢可塑性和启动炎症级联反应的原因，炎症级联反应在准备分娩时使宫颈成熟。对宫颈神经源性炎症时间进程的相关评估可能会预测妊娠的进展，并可能被证明有助于准确预测足月分娩的时间，或者在病理重塑的情况下，预示早产。因此，我们的发现有望为成熟的机制提供新的见解，并提供新的神经免疫治疗方法来促进宫颈扩张或抑制早产的发生。

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.