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

基本信息

  • 批准号:
    8891421
  • 负责人:
  • 金额:
    $ 32.34万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-07-15 至 2018-06-30
  • 项目状态:
    已结题

项目摘要

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)是一个主要的公共卫生问题,发病率高,相关费用高。目前,BPH患者的治疗相当统一。然而,对疾病过程和合并症在推动进展中的作用的真正理解应该允许将患者分层为亚组和更个性化的治疗方法,从而获得更好的疗效和更低的手术干预率。我们最近开发了一个由前列腺切除术中偶然发现的前列腺增生样本和前列腺增生进展到手术干预的患者组织组成的人类前列腺增生组织库。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,以解决与人类BPH的特定成分有关的问题,并将小鼠的反应与人类样本相关联。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BPH到严重的、医学难治性疾病的进展中的基因表达变化显示出一种模式,反映了在许多慢性炎症性疾病如银屑病、关节炎和炎症性肠病中观察到的变化。这些变化主要包括AP-1因子的基底细胞表达,特别是c-FOS,其与疾病进展至手术以及对5ARI治疗的抗性相关。其次,我们确定肥胖(Ob/Ob)和非肥胖糖尿病(NOD)小鼠表现出不同的前列腺肿大和炎症特征,反映了人类BPH的方面。这项工作的目的是确定AP-1应激反应在前列腺增生中的作用,并确定影响这些途径的药物方案是否会改变前列腺增生的进展。为了解决这些问题,提出了三个具体目标。具体目标1。确定特定的全身性应激是否影响AP-1信号传导和前列腺组织病理学。这一目的检验了以下假设:糖尿病、肥胖和炎症将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,并且这些变化将反映在人类样本中。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。本研究旨在验证以下假设:前列腺增生可通过继发于糖尿病、肥胖或炎症的AP-1因子激活对雄激素消融产生抗性。具体目标3。确定是否逆转肥胖,糖尿病或炎症减少前列腺增生。这一目标验证了通过逆转肥胖、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。

项目成果

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Simon W Hayward其他文献

MP35-02 <strong>BENIGN PROSTATIC HYPERPLASIA AND AUTOIMMUNE INFLAMMATORY DISEASES COINCIDENCE AND CONSEQUENCES</strong>
  • DOI:
    10.1016/j.juro.2016.02.1594
  • 发表时间:
    2016-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Jaclyn Pruitt;Jacqueline Petkewicz;Brittany Lapin;Omar E Franco;Brian T. Helfand;Charles B. Brendler;Chi-Hsiung Wang;Simon W Hayward
  • 通讯作者:
    Simon W Hayward
MP62-14 ACTIVATION OF ABERRANT ANDROGEN RECEPTOR SIGNALING IN CARCINOMA ASSOCIATED FIBROBLASTS INDUCES PROSTATE CANCER PROGRESSION
  • DOI:
    10.1016/j.juro.2016.02.922
  • 发表时间:
    2016-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Omar E Franco;Rodrigo Javier;Susan E Crawford;Gustavo E Ayala;Simon W Hayward
  • 通讯作者:
    Simon W Hayward

Simon W Hayward的其他文献

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{{ truncateString('Simon W Hayward', 18)}}的其他基金

Inflammatory Pathways in BPH/LUTS
BPH/LUTS 的炎症通路
  • 批准号:
    10205048
  • 财政年份:
    2018
  • 资助金额:
    $ 32.34万
  • 项目类别:
Leukocytic Phenotypes Associated with BPH Progression
与 BPH 进展相关的白细胞表型
  • 批准号:
    9789816
  • 财政年份:
    2018
  • 资助金额:
    $ 32.34万
  • 项目类别:
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:
    8782874
  • 财政年份:
    2014
  • 资助金额:
    $ 32.34万
  • 项目类别:
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:
    9136661
  • 财政年份:
    2014
  • 资助金额:
    $ 32.34万
  • 项目类别:
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
  • 财政年份:
    2014
  • 资助金额:
    $ 32.34万
  • 项目类别:
Obesity, Inflammation and BPH
肥胖、炎症和良性前列腺增生
  • 批准号:
    8566167
  • 财政年份:
    2012
  • 资助金额:
    $ 32.34万
  • 项目类别:
Obesity, Inflammation and BPH
肥胖、炎症和良性前列腺增生
  • 批准号:
    8446620
  • 财政年份:
    2012
  • 资助金额:
    $ 32.34万
  • 项目类别:
Obesity, Inflammation and BPH
肥胖、炎症和良性前列腺增生
  • 批准号:
    8549229
  • 财政年份:
    2012
  • 资助金额:
    $ 32.34万
  • 项目类别:
Obesity, Inflammation and BPH
肥胖、炎症和良性前列腺增生
  • 批准号:
    8705678
  • 财政年份:
    2012
  • 资助金额:
    $ 32.34万
  • 项目类别:
PPAR-gamma and BPH/LUTS
PPAR-gamma 和 BPH/LUTS
  • 批准号:
    8150405
  • 财政年份:
    2010
  • 资助金额:
    $ 32.34万
  • 项目类别:

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