Effects of estrogens on bladder pain

描述(申请人提供)：膀胱感觉神经的可塑性是伴随炎症状态的疼痛的基础，如间质性膀胱炎。我们最近对膀胱感觉神经元和尿路上皮细胞的研究揭示了雌激素在这两种类型的细胞中对信号传递过程的新颖和强大的作用。这些研究还表明，确定雌激素如何与炎症变化所必需的其他神经活性分子相互作用的重要性，如神经生长因子和三磷酸腺苷。总之，这项工作提高了确定新的药物策略的可能性，以靶向和控制该系统的可塑性，从而减少相关的疼痛。在这个项目中，我们提出了一组关于膀胱感觉神经元和尿路上皮细胞的全面研究，以进一步探讨雌激素在调节膀胱感觉神经元和尿路上皮细胞活动中的作用。我们的目标是确定雌激素影响急、慢性炎症后膀胱感觉通路可塑性的细胞机制。主要目的是：(1)了解雌激素在正常和炎症条件下影响膀胱对伤害性刺激的检测的机制；(2)确定雌激素如何影响其他因素对伤害性信号的调制。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、膜片钳电生理学和新型神经元-尿路上皮共培养系统。这些研究将有助于我们了解雌激素对膀胱传入神经的作用，特别是对膀胱伤害性感受的作用，并将为了解膀胱功能障碍，特别是与炎症有关的条件提供重要的见解。这可能有助于开发新的策略来对抗膀胱炎的痛苦后遗症或阻止疼痛扩散到其他盆腔内脏。

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.