Macrophage Migration Inhibitory Factor mediates bladder pain

我们的长期目标是发现盆腔疼痛的新治疗靶点。骨盆疼痛， 尤其是膀胱痛，也是间质性膀胱炎/膀胱痛的主要症状 综合征(IC/BPS)，大多数患者没有潜在的膀胱感染、病理或 受伤。调节骨盆疼痛的局部和中枢机制尚不完全清楚。 迫切需要纠正这种知识鸿沟，以开发出有效的小说 慢性盆腔疼痛的治疗靶点。 我们在这项应用中的总体目标是确定MIF的机制- 介导性膀胱痛觉过敏。我们的中心假设是MIF介导了膀胱 通过局部(膀胱)和中枢(脊髓)机制产生的痛觉过敏。 我们计划通过追求以下三个具体目标来检验我们的中心假设： 1.鉴定介导膀胱痛觉过敏的尿路上皮MIF受体。 基于上述公布的数据，我们的工作假设是，发布的MIF 作用于尿路上皮MIF受体，引起尿路上皮HMGB1释放和膀胱痛觉过敏。 2.确定MIF/HMGB1介导膀胱痛觉过敏的下游靶点。我们的 基于我们已发表的初步证据的工作假说是，阻断 MIF/HMGB1激活的下游信号通路可预防膀胱痛过敏。 3.明确持续性膀胱痛觉过敏的脊髓机制。 根据我们的初步数据，我们的工作假设是增加产量和 脊髓MIF的释放激活了脊髓HMGB1的释放，以维持膀胱疼痛。 为了实现这些目标，我们将使用啮齿动物模型进行研究 膀胱疼痛和使用人尿路上皮细胞的体外研究。我们将检查器官水平 和脊柱水平的膀胱疼痛的机制，同时专注于治疗持续性膀胱 疼痛。我们还将确定与持久性相关的新的腰骶肽/蛋白 膀胱疼痛。 这些研究的顺利完成可望产生积极影响。 因为确定的机制部件很可能会提供新的 用于治疗膀胱疼痛情况的外周和/或中央靶点。

Our long-term goal is to discover novel therapeutic targets for pelvic pain. Pelvic pain, bladder pain specifically, is also the cardinal symptom of interstitial cystitis/bladder pain syndrome (IC/BPS) where most patients show no underlying bladder infection, pathology, or injury. The local and central mechanisms that mediate pelvic pain are not fully understood. There is an urgent need to correct this knowledge gap so as to develop effective novel therapeutic targets for chronic pelvic pain. Our overall objective in this application is to determine the mechanisms of MIF- mediated bladder hyperalgesia. Our central hypothesis is that MIF mediates bladder hyperalgesia through local (bladder) and central (spinal) mechanisms. We plan to test our central hypothesis by pursuing the following three specific aims: 1. Identify urothelial MIF receptors that mediate bladder hyperalgesia. Based on the published data referred to above, our working hypothesis is that released MIF acts at urothelial MIF receptors to elicit urothelial HMGB1 release and bladder hyperalgesia. 2. Identify downstream targets of MIF/HMGB1 that mediate bladder hyperalgesia. Our working hypothesis, based on our published and preliminary evidence, is that blocking downstream signaling pathways activated by MIF/HMGB1 will prevent bladder hyperalgesia. 3. Identify spinal mechanisms that mediate persistent bladder hyperalgesia. Based on our preliminary data, our working hypothesis is that increased production and release of spinal MIF activates increased release of spinal HMGB1 to maintain bladder pain. In order to accomplish these aims we will conduct studies using rodent models of bladder pain and in vitro studies using human urothelial cells. We will examine organ-level and spinal-level mechanisms of bladder pain while focusing on treating persistent bladder pain. We will also identify novel lumbosacral peptides/proteins associated with persistent bladder pain. Succesful completion of these studies is expected to have a positive impact because it is probable that the identified components of the mechanism will provide new peripheral and/or central targets for therapeutic interventions in conditions of bladder pain.