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（BPH）和相关的下尿路症状（LUTS）是高发病率和相关成本的主要公共卫生问题。目前，对BPH患者的治疗相当均匀。但是，对疾病过程和合并症在驱动进展中的作用的真实了解应允许将患者分层为亚组和更个性化的治疗方法，从而提高疗效和较低的手术干预率。我们最近开发了一个人类BPH组织存储库，该存储库是由前列腺切除术中的附带BPH样品和BPH患者进行手术干预患者的组织的样本组成的。我们还研究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的特定组成部分有关的问题，并将鼠类对人类样本的反应相关联。我们最近的研究中出现了两个关键观察。首先，基因表达在从附带BPH到症状严重的医学上遭受抗性疾病的进展中发生了变化，表明了一种模式，它反映了在许多慢性炎症性疾病（例如牛皮癣，关节炎和炎症性肠病）中看到的变化。这些变化主要包括AP-1因子的基础细胞表达，特别是与疾病发展到手术以及对5ARI治疗的抗性有关的C-FOS。其次，我们确定肥胖（ob/ob）和非肥胖糖尿病（点头）小鼠表现出反映了人类BPH方面的前列腺增大和炎症的不同特征。拟议工作的目的是定义AP-1应激反应在前列腺增生中的作用，并确定影响此途径的药物方案是否改变了前列腺增生的进展。为了解决这些想法，提出了三个具体目标。特定目的1。确定特定的全身应激源是否影响AP-1信号传导和前列腺组织病理学。这个目的检验了以下假设：糖尿病，肥胖和炎症将导致AP-1因子激活的不同模式和小鼠前列腺的相关生长，并且这些变化将反映在人类样品中。具体目的2。确定组织特异性的AP-1因子是否会驱动炎症，前列腺增生和对治疗的耐药性。这个目的检验了以下假设：前列腺增生可以通过继发于糖尿病，肥胖或炎症的AP-1因子激活对雄激素消融具有抗性。具体目标3。确定逆转肥胖，糖尿病或炎症是否会减少前列腺增生。该目标检验了以下假设：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。

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.