Afferent and urothelial plasticity underlying bladder sensitization in prostatic inflammation

项目摘要/摘要 该方案的项目1名为“膀胱下的传入和尿路上皮可塑性 前列腺炎中的致敏作用“(项目负责人：吉村直树， 泌尿科)。前列腺炎被认为是良性疾病的一个重要组成部分。 前列腺增生症(BPH)与雄激素介导的“静止性”前列腺增大和 “动态的”α-肾上腺素能受体介导的肌肉张力。此前的研究也表明， 无症状前列腺炎与前列腺增生症的组织学进展 与下尿路症状(LUTS)的出现有关。因此，以下三个 主要目标利用匹兹堡提供的独特和创新的专业知识来确定详细的 术后膀胱过度活动、尿路上皮功能障碍及传入高兴奋性的机制 前列腺炎，据报道，它导致下尿路症状(LUTS)在 良性前列腺增生症(BPH)患者。我们还将致力于确定是否 局部应用神经生长因子反义、COX-2抑制或5-α-还原酶抑制可 逆转前列腺炎引发的病理过程。 在本申请中，我们建议扩展我们之前的NIDDK P20研究项目 (DK090919，PI：WANG)题为“匹兹堡大学良性前列腺规划中心 《增生研究》，通过对新机制和发展的批判性评估 前列腺炎引起的男性下尿路综合征的创新治疗方案。为了这个 目的：我们将利用局部注射阿司匹林诱发前列腺炎的动物模型。 福尔马林，这是在我们之前资助的P20项目中开发的。首先，我们将研究 膀胱功能和神经传入神经元功能/分子特性的变化 前列腺和/或膀胱以确定前列腺-膀胱传入交叉敏化的作用 在前列腺炎性下尿路综合征的发生中起重要作用。其次，我们将研究是否 前列腺炎导致膀胱尿路上皮功能障碍，这也是LUTS的原因之一 发展。最后，我们将试图澄清NGF在膀胱内的应用 反义结合脂质体靶向尿路上皮神经生长因子、环氧合酶-2抑制物 塞来昔布或5种α还原酶抑制剂(非那雄胺)可逆转功能和分子 前列腺癌引起的膀胱、尿路上皮和前列腺/膀胱传入通路的改变 大鼠模型的炎症反应。 研究计划的长期目标是确定新的有效目标 以及治疗与BPH相关的下尿路结石的方法。项目1将最大限度地利用 管理和组织核心资源的多样性，并与其他项目具有很强的协同作用。

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.