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/发展性项目申请。哈林顿核，一个向下投射到腰骶神经节前神经元的戊烷核，调节副交感神经向膀胱的流出。膀胱膨胀激活巴林顿核，然后协调内脏（收缩）和中枢（觉醒）对刺激的反应。促肾上腺皮质激素释放因子（CRF）是巴灵顿氏核神经元中的一种重要的神经递质，因此可以调节泌尿功能。此外，CRF的药理学操作可能为泌尿功能障碍提供一种新的治疗方法。尽管其在脑桥排尿回路中占有重要地位，但CRF在排尿中的作用以及操纵CRF对尿动力学功能的影响仍未被探索。该建议将确定CRF在桥脑-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梗阻而受损的尿动力学功能（AIM 2）。此外，将确定部分梗阻对脑桥排尿通路组成部分的影响（AIM 3）。膀胱术将用于量化脊髓CRF受体选择性激活或拮抗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，我们将量化膀胱梗阻对Barrington’s核神经元单个单位活性、Barrington’s核神经元中CRF mRNA表达和脊髓中CRF-受体mRNA表达的影响。这些研究结合了泌尿外科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认识。

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.