Preclinical phenotypic modeling of chronic urologic pelvic pain

慢性泌尿科盆腔疼痛的临床前表型模型

基本信息

批准号：
10599973
负责人：
Jennifer J DeBerry
金额：
$ 32.67万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10599973
关键词：
Address Adult Adverse event Afferent Neurons Anatomy Animal Model Animals Behavior Biological Response Modifiers Bladder CNS processing Chronic Chronic Prostatitis Chronic stress Clinical Clinical Data Complex Coupled Development Disease Disease model Electrophysiology (science)Emotional Esthesia Event Exposure to Future Genetic Genitourinary system Goals Histologic Hypersensitivity In Vitro Individual Inflammation Interstitial Cystitis Knowledge Lead Life Maintenance Measures Mediator Modeling Musculoskeletal Neonatal Neuroanatomy Neurons Neuropeptides Nociception Opioid Optics Organ Pain Pathogenesis Pathologic Pathology Pathway interactions Patient-Focused Outcomes Pelvic Pain Pelvic floor structure Pelvis Peripheral Peripheral Nerves Peripheral Nervous System Persons Phenotype Population Posterior Horn Cells Pre-Clinical Model Predisposition Prevalence Process Property Reflex action Rodent Model Sensory Spinal Spinal Cord Stress Stressful Event Structure Study models Subgroup System Techniques Testing Therapeutic Intervention Tissues Transducers Trauma United States Urodynamics Vertebral column Visceral Woman acute stress afferent nerve chronic pelvic pain clinically relevant dorsal horn early experience epidemiologic data experience extracellular human model improved in vivo information gathering innovation insight maternal separation men mouse genetics neural neurochemistry neurophysiology novel novel therapeutic intervention optogenetics patch clamp patient oriented physical insult postnatal development pre-clinical receptor response sensory system targeted treatment therapeutically effective treatment strategy urologic urologic chronic pelvic pain syndrome

项目摘要

PROJECT SUMMARY/ABSTRACT Hypersensitivity of the urogenital organs and pelvic region is associated with urologic chronic pelvic pain syndrome (UCPPS; inclusive of interstitial cystitis/painful bladder syndrome and chronic prostatitis). Evidence from animal models demonstrates that central nervous system processing of urogenital/pelvic sensory information may be modified individually by (i) neonatal events that occur during sensory development and that permanently alter neuroanatomical substrates, or (ii) adverse events, such as stress or trauma, experienced during development or adulthood. Both of these phenomena have a high degree of clinical relevance, and there is good reason to believe that consequential alterations in the phenotype and function of primary afferent neurons innervating the urogenital and pelvic region are critical for the development of hypersensitivity and, thus, would serve as targets for therapeutic intervention. The long-term goal of this project is to systematically study changes in primary afferent-to-spinal cord sensory processing of somatic and visceral urogenital structures in clinically relevant animal models of UCPPS. The objective of the current proposal is to systematically examine the effects of neonatal bladder inflammation (NBI) or maternal separation (NMS), alone and in combination with an adult insult of the same class (bladder re-inflammation, acute or chronic stress), on urogenital hypersensitivity and/or widespread pain. The guiding hypothesis that serves as the basis of this proposal is that experiencing early life inflammation or stress alters distinct subclasses of urogenital primary afferent and spinal dorsal horn neurons that, in turn, inhibit or augment urogenital sensitivity in the context of a secondary adult exposure to inflammation or stress. This hypothesis will be addressed in three specific aims using: 1) in vivo reflex behaviors coupled with optogenetic targeting of stratified neuronal populations to determine how NBI or NMS alter primary afferent- driven reflex behaviors, 2) patch-clamp and extracellular in vivo electrophysiology to characterize functional activity within urogenital afferent and spinal dorsal horn neuronal pathways following NBI or NMS, and 3) neurochemistry and optogenetics to identify neurochemical mediators and receptors/transducers in urogenital tissues, primary afferent neurons, and spinal dorsal horn involved in the development of pelvic hypersensitivity.

项目摘要/摘要泌尿生殖器官和骨盆区域的超敏反应与泌尿科慢性骨盆疼痛有关综合征（UCPPS；包括间质性膀胱炎/疼痛膀胱综合征和慢性前列腺炎）。证据从动物模型中表明，泌尿生殖器/骨盆感觉的中枢神经系统处理信息可以通过（i）感官发展过程中发生的新生儿事件单独修改，并且永久改变神经解剖底物，或（ii）经历的不良事件，例如压力或创伤在发展或成年期间。这两种现象都具有高度的临床相关性，并且是相信原发性传入神经元表型和功能的后果改变是充分的理由支配泌尿生殖器和骨盆区域对于超敏反应的发展至关重要，因此将作为治疗干预的靶标。该项目的长期目标是系统地研究变化在临床上的体细胞和内脏泌尿生殖结构的一级传入到脊髓感觉过程中 UCPP的相关动物模型。当前建议的目的是系统地检查效果新生儿膀胱炎症（NBI）或母体分离（NMS），单独并与成人结合对泌尿生殖性超敏反应和/或广泛的痛苦。作为该提议的基础的指导假设是经历早期的生活炎症或压力改变了泌尿生殖器原发性传入和脊柱背角神经元的不同亚类反过或压力。该假设将在三个特定目的中解决：1）体内反射行为与分层神经元种群的光遗传学靶向，以确定NBI或NMS如何改变原发性传入 - 驱动的反射行为，2）斑块夹和细胞外体内电生理学，以表征功能 NBI或NMS之后的泌尿生殖器传入和脊髓背角神经途径的活性，3）神经化学和光遗传学，以识别泌尿生殖器中的神经化学介质和受体/传感器组织，原发性传入神经元和脊柱背角参与骨盆超敏反应的发展。