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

AP-1在良性前列腺增生发病机制和进展中的影响因素

• 批准号: 9316616
• 负责人: Simon W Hayward
• 金额: $ 33.93万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316616
• 关键词: Ablation; Address; Adrenergic Antagonists; Adverse effects; Affect; Aging; Androgen Receptor; Androgens; Arthritis; Autoimmunity; Automobile Driving; Back; Basal Cell; Benign Prostatic Hypertrophy; Biological Assay; Biology; Cell Proliferation; Chronic; Clinical; Comorbidity; Data; Diabetes Mellitus; Diabetic mouse; Diet; Disease; Disease Progression; Enzymes; Epithelial; Epithelial Cells; Epithelium; FOS gene; Future; Gene Expression; Gene Expression Profile; Glucocorticoids; Growth; Histopathology; Hormones; Human; Hyperplasia; Immune; Inbred NOD Mice; Infiltration; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Insulin; JUN gene; Leptin; Longitudinal Studies; Malignant neoplasm of prostate; Medical; Mesenchyme; Metabolic syndrome; Morbidity - disease rate; Mus; Obesity; Operative Surgical Procedures; Oxidoreductase; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Population; Process; Prostate; Prostatectomy; Prostatic; Prostatic hypertrophy; Psoriasis; Public Health; Pump; Recombinants; Refractory; Refractory Disease; Regimen; Resistance; Role; Sampling; Secondary to; Signal Transduction; Stress; Stromal Cells; Testing; Tissue Recombination; Tissues; Transcription Factor AP-1; Transgenic Mice; Transgenic Model; Work; biological adaptation to stress; cellular engineering; cost; diabetes control; human disease; human tissue; inhibitor/antagonist; lower urinary tract symptoms; male; mouse model; novel therapeutic intervention; patient stratification; personalized approach; public health relevance; repository; response; stressor; therapy resistant; tissue regeneration; tool

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.

描述(由申请人提供)：良性前列腺增生症(BPH)和相关的下尿路症状(LUTS)是一个主要的公共卫生问题，发病率高，相关成本高。目前，前列腺增生症患者得到的治疗相当统一。然而，对疾病过程和合并症在推动进展中的作用的真正了解应该允许将患者分层为亚组和更个性化的治疗方法，从而导致更好的疗效和更低的手术干预率。我们最近开发了一个人类BPH组织资料库，包括在前列腺切除术中发现的偶发BPH样本和来自BPH进展到手术干预的患者的组织样本。我们还调查了糖尿病和肥胖的小鼠模型如何反映人类BPH的特定方面。这提供了新的工具来解决与人类BPH特定成分相关的问题，并将小鼠对人类样本的反应联系起来。在我们最近的研究中出现了两个关键的观察结果。首先，从偶发性良性前列腺增生症到症状严重、药物难治性疾病的进展过程中，基因表达的变化显示出一种模式，反映了牛皮癣、关节炎和炎症性肠病等一些慢性炎症性疾病的变化。这些变化突出地包括AP-1因子的基底细胞表达，特别是c-fos，它们与疾病进展到手术有关，也与5ARI治疗的抵抗有关。其次，我们确定肥胖(Ob/Ob)和非肥胖糖尿病(NOD)小鼠表现出明显的前列腺增大和炎症特征，这些特征反映了人类BPH的某些方面。这项拟议工作的目的是确定AP-1应激反应在前列腺增生症中的作用，并确定影响这些途径的药物方案是否改变了前列腺增生症的进展。为了解决这些想法，提出了三个具体目标。明确目标1.确定特定的全身应激源是否影响AP-1信号转导和前列腺组织病理学。这一目标验证了一种假设，即糖尿病、肥胖和炎症将导致小鼠前列腺中AP-1因子激活和相关生长的不同模式，并且这些变化将在人类样本中反映出来。具体目的2.确定组织特异性AP-1因子是否会导致炎症、前列腺增生和对治疗的抵抗。这一目标验证了一种假说，即继发于糖尿病、肥胖症或炎症的AP-1因子的激活可以使前列腺增生对雄激素消融产生抵抗。明确目标3.确定逆转肥胖、糖尿病或炎症是否可以减少前列腺增生。这一目标验证了这样一个假设，即通过逆转肥胖、糖尿病或炎症来降低AP-1的活性将减少增生并恢复对治疗的敏感性。

项目成果

Tyrosine kinase inhibitor therapy prescribed for non-urologic diseases can modify PSA titers in urology patients

用于非泌尿科疾病的酪氨酸激酶抑制剂治疗可以改变泌尿科患者的 PSA 滴度

• DOI: 10.1002/pros.23730
• 发表时间: 2018
• 期刊: The Prostate
• 作者: Sasaki Takeshi;Franco Omar E.;Ohishi Kohshi;Filipovich Yana;Ishii Kenichiro;Crawford Susan E.;Takahashi Naoto;Katayama Naoyuki;Sugimura Yoshiki;Hayward Simon W.
• 通讯作者: Hayward Simon W.