Afferent and urothelial plasticity underlying bladder sensitization in prostatic inflammation

项目总结/摘要 该计划的项目1名为“膀胱的传入和尿路上皮可塑性 前列腺炎症的致敏作用”（项目负责人： 泌尿科）。前列腺炎症被认为是良性前列腺增生的重要组成部分。 前列腺增生（BPH），以及雄激素介导的“静态”前列腺肥大， “动态”α-肾上腺素受体介导的肌肉紧张。以前的研究也表明， 无症状前列腺炎症与组织学BPH的发展相关， 参与下尿路症状（LUTS）的出现。因此，以下三个 关键目标利用匹兹堡独特和创新的专业知识， 膀胱过度活动，尿路上皮功能障碍和传入过度兴奋的机制， 前列腺炎症，据报道，这有助于下尿路症状（LUTS）， 良性前列腺增生（BPH）患者。我们还将致力于确定 局部应用NGF反义、考克斯-2抑制或5α-还原酶抑制的治疗可 逆转前列腺炎症引发的病理过程。 在这个应用中，我们建议扩展我们以前的NIDDK P20研究项目 （DK 090919，PI：Wang），题为“匹兹堡大学良性前列腺规划中心 增生研究”，通过对新机制的批判性评价和 前列腺炎症引起的男性LUTS的创新治疗选择。为此 目的：本研究拟利用前列腺局部注射前列腺素A诱导的前列腺炎症动物模型， 福尔马林，这是在我们以前资助的P20项目中开发的。首先，我们会研究 膀胱功能和支配膀胱的传入神经元的功能/分子特性的变化 前列腺和/或膀胱，以确定前列腺-膀胱传入交叉致敏的作用 在前列腺炎症引起的下尿路症状的发展中起作用。第二，我们将研究 前列腺炎症诱导膀胱尿路上皮功能障碍，这也有助于LUTS 发展最后，我们将试图阐明膀胱内应用神经生长因子是否 与靶向尿路上皮NGF产生的脂质体偶联的反义考克斯-2抑制剂 （塞来昔布）或5α-还原酶抑制剂（非那肽）可以逆转功能和分子 前列腺刺激引起的膀胱、尿道和前列腺/膀胱传入通路的变化 在大鼠模型中的炎症。 该研究计划的长期目标是确定新的有效目标 和用于治疗与BPH相关的LUTS的方法。项目1将最大限度地利用 该项目充分利用了行政核心和组织核心的资源，并与其他项目有很强的协同作用。

Project Summary/Abstract Project 1 of the program is entitled "Afferent and urothelial plasticity underlying bladder sensitization in prostatic inflammation" (Project Leader: Naoki Yoshimura, Department of Urology). Prostatic inflammation is considered to be an important component of benign prostate hyperplasia (BPH) in addition to androgen-mediated ``static'' prostate enlargement and ‘‘dynamic’’ α-adrenoceptor–mediated muscle tension. Previous studies also suggest that asymptomatic prostatic inflammation associated with the development of histological BPH in involved in the emergence of lower urinary tract symptoms (LUTS). Thus, the following three key aims utilize unique and innovative expertise available in Pittsburgh to identify the detailed mechanisms of bladder overactivity, urothelial dysfunction and afferent hyperexcitability after prostatic inflammation, which reportedly contribute to lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH). We will also aim to determine whether treatments of local NGF antisense application, COX-2 inhibition or 5α-reductase inhibition can reverse the pathological processes initiated by prostatic inflammation. In this application, we propose to extend our previously NIDDK P20 research project (DK090919, PI: Wang) entitled “University of Pittsburgh Planning Center for Benign Prostate Hyperplasia Research”, by critical evaluation of new mechanisms and development of innovative treatment options for male LUTS induced by prostatic inflammation. For this purpose, we will utilize an animal model of prostatic inflammation induced by local injection of formalin, , which was developed in our previously funded P20 project. First, we will study the changes in bladder function and functional/molecular properties of afferent neurons innervating the prostate and/or bladder to identify the role of prostate-to-bladder afferent cross sensitization in the development of LUTS due to prostatic inflammation. Secondly, we will examine whether prostatic inflammation induces bladder urothelial dysfunction, which also contributes to LUTS development. Lastly, we will seek to elucidate whether intravesical application of NGF antisense conjugated with liposomes targeting urothelial NGF production, COX-2 inhibitors (celecoxib) or 5α-reductase inhibitors (finasteride) can reverse functional and molecular changes in the bladder, urothelium and prostate/bladder afferent pathways initiated by prostatic inflammation in the rat model. The long-term objectives of the research program are to identify new and effective targets and methods for the treatment of LUTS associated with BPH. Project 1 will maximize the uses of the resources of Administrative and Tissue Cores, and has strong synergy with other projects.