Bladder Regulation by Corticotropin-Releasing Factor

描述（由申请人提供）：这是一份针对PA-03-136“膀胱和下尿路基础研究”的探索性/开发性项目申请。哈灵顿核是一个戊烷核，具有向腰骶节前神经元的下行投射，调节向膀胱的副交感神经流出。膀胱扩张激活巴林顿核，然后协调内脏（收缩）和中枢（唤醒）对刺激的反应。促肾上腺皮质激素释放因子（CRF）是巴林顿核神经元中一种重要的神经递质，因此有望调节泌尿功能。此外，CRF的药理学操作可能提供一种新的治疗泌尿功能障碍。尽管CRF在桥脑排尿回路中的重要性，但其在排尿中的作用以及操作CRF对尿动力学功能的影响仍未得到研究。该提案将确定CRF在脑桥-脊髓回路中的作用（AIM 1），以及在脊髓中操作CRF是否可以改善因部分阻塞而受损的尿动力学功能（AIM 2）。此外，部分梗阻对脑桥排尿通路的影响将被确定（AIM 3）。膀胱测压将用于量化脊髓中CRF受体的选择性激活或拮抗作用对膀胱通畅或部分阻塞的未麻醉大鼠尿动力学的影响。相反，将量化膀胱阻塞对巴林顿核神经元的单个单位活性、巴林顿核神经元中的CRF mRNA表达和脊髓中的CRF受体mRNA表达的影响。这些研究结合了泌尿学和基础神经科学实验室的互补专业知识，以增加我们对正常和病理状态下泌尿功能中枢调节的了解。

DESCRIPTION (provided by applicant): This is an application for an Exploratory/Developmental Project in response to PA-03-136,"Basic Research in the Bladder and Lower Urinary Tract". Harrington's nucleus, a pentane nucleus with descending projections to lumbosacral preganglionic neurons, regulates parasympathetic outflow to the bladder. Bladder distention activates Barrington's nucleus, which then coordinates visceral (contraction) and central (arousal) responses to the stimulus. Corticotropin-releasing factor (CRF) is a prominent neurotransmitter in Barrington's nucleus neurons and is therefore poised to modulate urinary function. Moreover, pharmacological manipulation of CRF may provide a novel treatment of urinary dysfunctions. In spite of its prominence in the pontine micturition circuit, the role of CRF in micturition and the impact of manipulating CRF on urodynamic function remain unexplored. This proposal will determine the role of CRF in the pontine-spinal circuit (AIM 1) and whether manipulation of CRF in the spinal cord can improve urodynamic function that has been compromised by partial obstruction (AIM 2). Additionally, the impact of partial obstruction on components of the pontine micturition pathway will be identified (AIM 3). Cystometry will be used to quantify effects of selective activation or antagonism of CRF receptors in the spinal cord on urodynamics in unanesthetized rats with unobstructed or partially obstructed bladder. Conversely, the impact of bladder obstruction on single unit activity of Barrington's nucleus neurons, CRF mRNA expression in Barrington's nucleus neurons and CRF- receptor mRNA expression in the spinal cord will be quantified. These studies unite complementary expertise from laboratories in urology and basic neuroscience to increase our knowledge of the central regulation of urinary function in normal and pathological state.