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

• 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
• 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

(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.

（请保持文字，不要PDF） 膀胱疼痛综合征（BPS）/间质性膀胱炎（IC）是一种慢性盆腔疼痛疾病，其特征为耻骨上盆腔疼痛，伴有至少一种泌尿系统症状。压力会加重BPS/IC的症状。尽管进行了大量的研究，但我们缺乏对排尿反射的结构和功能变化如何与BPS/IC相关以及压力如何加剧症状，从而阻碍有效治疗的了解。扩展我们以前的合作，整合我们不同的科学学科，并结合我们独特的实验室优势，我们将使用重复变量压力（RVS）和环磷酰胺（CXN）损伤/炎症模型来测试总体假设，即压力和损伤引起的中枢排尿和外周感觉回路变化导致的排尿频率和骨盆疼痛反应增加，分别，反映PACAP/PAC 1受体介导的信号传导和神经可塑性，以产生促兴奋状态。基于我们以前的工作，我们将评估PACAP/PAC 1 R通路之间的适应不良交叉可能如何导致应激诱导的膀胱功能障碍和盆腔疼痛。目标1：为了测试在没有直接膀胱损伤的情况下，RVS是否诱导与中枢神经回路中的PACAP/PAC 1 R神经化学可塑性相关的排尿反射的变化。假设：我们以前的研究已经证明了神经肽的表型可塑性，包括压力挑战后PACAP/PAC 1 R表达的变化。与这些反应相协调，我们预计RVS和RVS挑战将类似地导致中枢排尿通路PACAP/PAC 1 R可塑性改变排尿和疼痛反应。这些研究在以下方面具有重要意义：（1）获得了有助于应激和损伤/炎症诱导的排尿行为和盆腔疼痛变化的潜在结构和功能变化的机制见解;（2）心理应激对膀胱功能和盆腔感觉的中枢回路的影响，以及（3）鉴定PACAP/PAC 1受体介导的信号传导作为应激和损伤/炎症的新靶点，引起膀胱功能障碍和骨盆疼痛。