NEURAL REGULATION OF PREPARTUM CERVICAL RIPENING

产前宫颈成熟的神经调节

• 批准号: 7758823
• 负责人: STEVEN M YELLON
• 金额: $ 19.85万
• 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 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7758823
• 关键词: Address; Biochemical; Biomechanics; Birth; Brain; Cells; Cervical Ripening; Cervix Uteri; Characteristics; Chemicals; Clinical; Collagen; Cutaneous; Denervation; Edema; Elastases; Fiber; Gatekeeping; Histologic; Human; Hypertrophy; Immigration; Immune; Incidence; Inflammation; Inflammatory; Labor Onset; Mediating; Methods; Mus; Nerve Fibers; Neurogenic Inflammation; Neuronal Plasticity; Neurons; Neurotransmitters; Nitric Oxide; Operative Surgical Procedures; Pathway interactions; Pelvis; Phase Transition; Play; Pregnancy; Premature Birth; Preparation; Process; Progesterone; Property; Rattus; Reaction; Relative (related person); Relaxation; Reporting; Research; Rodent; Role; Sensory; Signal Transduction; Skin; Spinal Cord; Structure; System; Testing; Therapeutic; Time; Tracer; Withdrawal; base; collagenase; density; experience; innovation; insight; leukocyte activation; macrophage; nerve supply; neural tract; neuroregulation; novel; pregnant; relating to nervous system; steroid hormone

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.

描述（由申请人提供）：子宫颈成熟的细胞和生化变化发生在出生前。最近的研究结果表明，成熟过程与炎症;移民和激活的白细胞一致的发现增加的局部神经支配和可塑性的中央连接到小鼠子宫颈的出生前一天。基于这些发现，本提案的主要目的是检验神经信号对子宫颈重塑机制至关重要的假设，为分娩做准备。在研究计划中采取了系统的方法，重点关注盆腔，腹下和迷走神经通路的贡献，它们的感觉和自主神经投射，以及孕激素戒断对妊娠结束时子宫颈炎症和重塑的作用。方法开发估计神经纤维密度和跟踪神经投射从宫颈到大脑的小鼠和大鼠。虽然中央连接到非妊娠子宫颈已被报道，准确地确定哪些途径是负责增加一氧化氮产生纤维和神经肽能纤维在妊娠结束时是本建议的主要目标。将采取三种方法来了解神经支配对重塑妊娠宫颈的重要性：在具体目标1中，将从组织学上评估手术去神经支配的影响，以确定每条途径对增强妊娠宫颈神经纤维密度的相对贡献。出生前。去神经特定的感觉传入，但不是其他神经的预测，建议破坏宫颈成熟。第二项研究将探讨化学神经切除术消除的特定神经递质阻断宫颈重塑的可能性。在特定目标2中，逆行神经束示踪剂将用于研究宫颈、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标，调节神经投射和他们的活动在子宫颈之前，提出依赖于功能性的孕酮撤退。孕酮的营养作用降低，被认为可诱导局部神经增殖、中枢可塑性和炎症级联反应的启动，从而使子宫颈成熟，为分娩做准备。对宫颈神经源性炎症的时间进程进行相关评估可以预测妊娠的进展，并且可以被证明有助于准确预测足月分娩的时间，或者在病理性重塑的情况下，可以指示早产。因此，我们的研究结果有望提供有关成熟机制的新见解和新的神经免疫治疗方法，以促进宫颈扩张或抑制早产的发生率。