Effects of estrogens on bladder pain

描述（由申请人提供）：膀胱感觉神经支配的可塑性是伴随炎症状态（如间质性膀胱炎）的疼痛的基础。我们最近对膀胱感觉神经元和尿路上皮的研究揭示了雌激素对这两种细胞的信号传导过程的新颖而强大的作用。这些研究还表明，确定雌激素如何与炎性变化中不可或缺的其他神经活性分子（如神经生长因子和ATP）相互作用的重要性。总之，这项工作提出了确定新的药理策略的可能性，以靶向和控制该系统的可塑性，从而减少相关的疼痛。本项目拟开展膀胱感觉神经元和尿路上皮细胞的综合研究，进一步探讨雌激素在调节膀胱感觉神经元和尿路上皮活性中的作用。我们的目标是确定在急性和慢性炎症后，雌激素影响膀胱感觉通路可塑性的细胞机制。主要目的是：(1)了解在正常和炎症条件下，雌激素影响膀胱对有害刺激的检测的机制；(2)确定雌激素如何通过其他因素影响伤害感受信号的调节。为了实现这些目标，该项目将结合一系列实验方法，包括细胞信号研究、成人膀胱感觉神经元培养、免疫荧光和图像分析、膜片钳电生理学和一种新型神经元-尿路上皮共培养系统。这些研究将使我们进一步了解雌激素对膀胱传入神经支配的作用，特别是对膀胱伤害感觉的作用，并将为膀胱功能障碍，特别是涉及炎症的情况提供重要的见解。这可能有助于开发新的策略来抵消膀胱炎症的疼痛后遗症或阻止疼痛扩散到其他盆腔脏器。

DESCRIPTION (provided by applicant): Plasticity in the sensory innervation of the urinary bladder underlies the pain accompanying inflammatory states, such as interstitial cystitis. Our recent studies on bladder sensory neurons and urothelium have revealed novel and powerful actions of estrogens on signaling processes in both types of ceils. These studies have also indicated the importance of defining how estrogens interact with other neuroactive molecules integral to inflammatory changes, such as nerve growth factor and ATP. Together, this work raises the possibility of identifying new pharmacological strategies for targeting and controlling plasticity in this system and hence reducing the associated pain. In this project we propose a comprehensive group of studies on bladder sensory neurons and urothelial cells to further explore the role of estrogens in modulating the activity of bladder sensory neurons and urothelium. Our goal is to identify the cellular mechanisms by which estrogens influence of the plasticity of bladder sensory pathways after acute and chronic inflammation. The major aims are: (1) To understand the mechanism by which estrogens affect the detection of noxious stimuli by the bladder, under normal and inflamed conditions; (2) To determine how estrogens affect the modulation of nociceptive signaling by other factors. To achieve these aims the project will combine an array of experimental approaches, including cell signaling studies, cultures of adult bladder sensory neurons, immunofluorescence and image analysis, patch clamp electrophysiology and a novel neuron-urothelium co-culture system. These studies will lead to advances in our understanding of estrogen actions on bladder afferent innervation, especially bladder nociception, and will provide important insights into bladder dysfunction, especially conditions involving inflammation. This may assist with the development of new strategies to counteract painful sequelae of bladder inflammation or blocking spread of pain to other pelvic viscera.