AP-1 Factors in the Pathogenesis and Progression of Benign Prostatic Hyperplasia

描述（由申请人提供）：良性前列腺增生（BPH）和相关的下尿路症状（LUTS）是一个主要的公共卫生问题，具有高发病率和相关费用。目前，BPH患者的治疗相当统一。然而，真正了解疾病过程和合并症在推动进展中的作用，应该允许将患者分层为亚组，并采用更个性化的治疗方法，从而提高疗效和降低手术干预率。我们最近开发了一个人类BPH组织库，由前列腺切除术中发现的偶然BPH样本和BPH进展到手术干预的患者的组织组成。我们还研究了糖尿病和肥胖小鼠模型如何反映人类BPH的特定方面。这为解决与人类BPH的特定成分有关的问题以及将小鼠反应与人类样本相关联提供了新的工具。在我们最近的研究中出现了两个关键的观察结果。首先，从偶发性前列腺增生到症状严重的难治性疾病的过程中，基因表达的变化显示出一种模式，反映了许多慢性炎症性疾病（如牛皮癣、关节炎和炎症性肠病）的变化。这些显著的变化包括AP-1因子的基底细胞表达，特别是c-FOS，这与疾病进展到手术以及对5ARI治疗的耐药性有关。其次，我们确定肥胖（Ob/Ob）和非肥胖糖尿病（NOD）小鼠在前列腺增大和炎症方面表现出不同的特征，这反映了人类前列腺增生的各个方面。本研究的目的是确定AP-1应激反应在前列腺增生中的作用，并确定影响这些通路的药物方案是否会改变前列腺增生的进展。为了解决这些想法，提出了三个具体目标。具体目标确定特异性系统性应激源是否影响AP-1信号传导和前列腺组织病理学。该研究的目的是验证一种假设，即糖尿病、肥胖和炎症会在小鼠前列腺中引起AP-1因子激活和相关生长的不同模式，而这些变化将在人类样本中得到反映。具体目标2。确定组织特异性AP-1因子是否驱动炎症、前列腺增生和对治疗的抵抗。本研究旨在验证前列腺增生可通过继发于糖尿病、肥胖或炎症的AP-1因子激活而抵抗雄激素消融的假设。具体目标3。确定逆转肥胖、糖尿病或炎症是否能减少前列腺增生。该研究旨在验证通过逆转肥胖、糖尿病或炎症来降低AP-1活性将减少增生并恢复对治疗的敏感性的假设。

DESCRIPTION (provided by applicant): Benign prostatic hyperplasia (BPH) and associated Lower Urinary Tract Symptoms (LUTS) are a major public health problem with high morbidity and associated costs. At present, BPH patients are treated fairly uniformly. However, a true understanding of the disease process and the role of comorbidities in driving progression should allow stratification of patients into sub-groups and a more personalized approach to therapy, leading to better efficacy and lower rates of surgical intervention. We have recently developed a human BPH tissue repository composed of samples of incidental BPH found at prostatectomy and of tissue from patients whose BPH had progressed to surgical intervention. We also investigated how mouse models of diabetes and obesity reflect specific aspects of human BPH. This provides new tools to address questions relating to specific components of human BPH and to correlate murine responses to human samples. Two key observations have emerged in our recent studies. First, gene expression changes in the progression from incidental BPH to symptomatically severe, medically-refractory disease showed a pattern that mirrored changes seen in a number of chronic inflammatory conditions such as psoriasis, arthritis and inflammatory bowel disease. These changes prominently included basal cell expression of AP-1 factors, notably c-FOS, which were associated with disease progression to surgery and also with resistance to 5ARI therapy. Second, we determined that obese (Ob/Ob) and non-obese diabetic (NOD) mice show distinct features of prostatic enlargement and inflammation that mirror aspects of human BPH. The purpose of the proposed work is to define the role of AP-1 stress responses in prostatic hyperplasia and to determine whether drug regimens that affect such pathways alter the progression of prostatic hyperplasia. To address these ideas three Specific Aims are proposed. Specific Aim 1. Determine whether specific systemic stressors affect AP-1 signaling and prostate histopathology. This aim tests the hypothesis that diabetes, obesity and inflammation will give rise to distinct patterns of AP-1 factor activation and associated growth in the mouse prostate and that these changes will be reflected in human samples. Specific Aim 2. Determine whether tissue-specific AP-1 factors drive inflammation, prostatic hyperplasia and resistance to therapy. This aim tests the hypothesis that prostatic hyperplasia can be rendered resistant to androgen ablation by AP-1 factor activation secondary to diabetes, obesity or inflammation. Specific Aim 3. Determine whether reversing obesity, diabetes or inflammation reduces prostatic hyperplasia. This aim tests the hypothesis that reducing AP-1 activity by reversing obesity, diabetes or inflammation will reduce hyperplasia and restore sensitivity to therapy.