PACAP/PAC1 receptor signaling in micturition neurocircuits: effects of stress and injury/inflammation

排尿神经回路中的 PACAP/PAC1 受体信号传导：压力和损伤/炎症的影响

基本信息

批准号：
10774523
负责人：
SAYAMWONG E. HAMMACK
金额：
$ 30.6万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10774523
关键词：
Address Afferent Neurons Behavior Bladder Bladder Dysfunction Cell Nucleus Chronic Chronic stress Clinical Collaborations Complex Control Animal Cyclophosphamide Discipline Distal Esthesia FOS gene Increased frequency of micturition Inflammation Injury Interstitial Cystitis Laboratories Lateral Link Micturition Reflex Modeling Neuronal Plasticity Neurons Neuropeptides PACAPR-1 protein Pain Pain Disorder Pathway interactions Pattern Pelvic Pain Pelvis Peripheral Phenotype Pontine structure Psychological Stress Publishing Receptor Signaling Research Role Sensory Signal Transduction Signs and Symptoms Spinal Cord Stress Structure Structure of terminal stria nuclei of preoptic region Symptoms Testing Urination Work biological adaptation to stress chronic pelvic pain effective therapy innovation insight interdisciplinary approach multidisciplinary neural circuit neurochemistry novel parabrachial nucleus pituitary adenylate cyclase activating polypeptide receptor-mediated signaling response stressor urinary

项目摘要

(PLEASE KEEP IN WORD, DO NOT PDF) Bladder Pain Syndrome (BPS)/ Interstitial Cystitis (IC) is a chronic pelvic pain disorder characterized by suprapubic, pelvic pain with at least one urinary symptom. Stress exacerbates symptoms of BPS/IC. Despite intense research, we lack understanding of how structural and functional changes in the micturition reflex are linked to BPS/IC and how stress exacerbates symptoms, thus impeding effective therapies. Expanding upon our previous collaborations, integrating our diverse scientific disciplines, and combining our unique laboratory strengths, we will use a repeated variate stress (RVS) and cyclophosphamide (CYP) injury/inflammation models to test the overall hypothesis that increases in urinary frequency and pelvic pain responses from stress- and injury-induced changes in central micturition and peripheral sensory circuits, respectively, reflect PACAP/PAC1 receptor-mediated signaling and neuroplasticity to engender a pro-excitatory state. Building from our previous work, we will assess how maladaptive intersections between the PACAP/PAC1R pathways may be contributory to stress-induced urinary bladder dysfunction and pelvic pain. Aim 1: To test whether RVS, in the absence of direct urinary bladder insults, induces changes in micturition reflexes that are associated with PACAP/PAC1R neurochemical plasticity in central neural circuits. Hypothesis: Our previous studies have demonstrated neuropeptide phenotypic plasticity, including changes in PACAP/PAC1R expression after stress challenges. Coordinate with these responses, we anticipate that RVS and CYP challenges will similarly result in central micturition pathway PACAP/PAC1R plasticity to alter voiding and pain responses. These studies are significant in the: (1) mechanistic insight gained of underlying structural and functional changes contributory to stress- and injury/inflammation-induced changes in voiding behavior and pelvic pain; (2) influence of psychological stress on central circuits underlying bladder function and pelvic sensation and (3) identification PACAP/PAC1 receptor-mediated signaling as a novel target for stress- and injury/inflammation-induced urinary bladder dysfunction and pelvic pain.

（请保持言语，不要PDF）膀胱疼痛综合征（BPS）/间质性膀胱炎（IC）是一种慢性骨盆疼痛障碍，其特征是上肠上，骨盆疼痛至少一种尿症状。压力加剧了BPS/IC的症状。尽管进行了激烈的研究，但我们对排尿反射的结构和功能变化如何与BPS/IC有关，以及压力如何加剧症状，从而阻碍有效的疗法。扩大我们以前的合作，整合多样化的科学纪律并结合我们独特的实验室优势，我们将使用重复的变化压力（RVS）和环磷酰胺（CYP）损伤/炎症模型来测试整体假设，以增加尿频和骨盆诱发的促进型和per症的促进型和per症的促进性变化，并诱发的中心变化，并伴有中心症状，并反射出偏移症状，并反射出症状的变化。受体介导的信号传导和神经可塑性导致促兴趣状态。我们将根据我们以前的工作建立，我们将评估PACAP/PAC1R途径之间的不良适应性交集可能导致压力诱导的尿道膀胱功能障碍和骨盆疼痛。目标1：测试RV在没有直接尿道损伤的情况下是否引起与PACAP/PACAP/PAC1R神经化学可塑性相关的排尿反射变化。假设：我们以前的研究表明了神经肽表型可塑性，包括压力挑战后的PACAP/PAC1R表达的变化。与这些响应进行协调，我们预计RV和CYP挑战将同样导致中央排尿途径PACAP/PAC1R可塑性改变空白和疼痛反应。这些研究在：（1）基本的结构和功能变化中获得的机械洞察力有助于压力和损伤/炎症引起的空隙行为和骨盆疼痛的变化；（2）心理压力对膀胱功能和骨盆感觉的基础电路的影响以及（3）鉴定PACAP/PAC1受体介导的信号传导是应激和损伤/炎症诱导的尿液膀胱功能障碍和骨盆疼痛的新目标。