Role of Inflammation and Epigenetics in Benign Prostate Pathology

描述(申请人提供)：与良性前列腺增生和前列腺炎相关的下尿路症状对生活质量有深远的影响。与良性前列腺疾病同时发生的尿路排尿综合征尤其令人烦恼，在极端情况下，可能会危及生命。这项工作的首要目标是明确炎症在良性前列腺病理中的作用，重点是对上皮细胞基因表达、表观遗传学和分化的长期影响。开展这项研究的基本原理是，我们假设炎症事件对前列腺生长和分化的持久影响是由上皮细胞的表观遗传学变化介导的，而表观基因组目前是一个可获得的药物靶点。因此，通过成功完成这里提出的工作来证实这一假设，将通过告知现有药物的新的治疗应用而迅速转化为患者的利益。来自临床研究的证据强烈地表明细胞因子的异常表达与良性前列腺疾病的病因有关。众所周知，细胞因子是炎症反应的主要介质，但也可以对上皮细胞和基质细胞产生直接影响。为了确定前列腺炎性细胞因子表达增加的后果，将建立一个条件转基因小鼠模型并对其进行鉴定。我们将分析上调的ILI7和ILIp对前列腺癌炎症、形态、基因表达和表观遗传标志的影响。在小鼠模型中，盆腔疼痛的程度与前列腺炎的程度也将被确定。同时，来自开放性前列腺癌和根治性前列腺炎性切除病例的人类患者材料将被描述。在有和没有下尿路症状的患者的样本中，反应性和正常上皮中的基因表达和DNA甲基化的模式将被量化。这些分析将为炎症对人前列腺上皮细胞转录组和表观基因组的影响提供新的见解，在未来的研究中可以在诊断和治疗方面加以利用，以减少与良性前列腺疾病及其同时发生的排尿综合征相关的发病率。 公共卫生相关性：这项拟议的工作与人类健康直接相关，因为它将定义前列腺疾病中发生的细胞变化。现有的药物类别可能有效地抵消这些变化，因此可能有效地缓解良性前列腺增生症和前列腺炎患者常见的下尿路症状。

DESCRIPTION (provided by applicant): Lower urinary tract symptoms associated with benign prostatic hyperplasia and prostatitis have a profound impact on quality of life. Urinary tract voiding syndromes that occur in concert with benign prostate disorders are particularly bothersome and, in extreme cases, can be life threatening. The overarching goal of the work proposed here is to define the role of inflammation in benign prostate pathologies, focusing on long-term effects on epithelial cell gene expression, epigenetics, and differentiation. The rationale for undertaking this study is that we hypothesize that the enduring effects of inflammatory events on prostate growth and differentiation are mediated by epigenetic changes in the epithelium, and the epigenome is currently an accessible drug target. Thus, confirmation of this hypothesis by successful completion of the work proposed here would be rapidly translated into patient benefits by informing new therapeutic applications of existing drugs. Evidence from clinical studies strongly implicates aberrant expression of cytokines in etiology of benign prostatic disease. Cytokines are well known to be primary mediators of the inflammatory response but can also have direct effects on epithelial and stromal cells. To determine the consequences of increased proinflammatory cytokine expression in the prostate, a conditional transgenic mouse model will be developed and characterized. The effects of up-regulated ILI 7 and ILI p on prostate inflammation, morphology, gene expression, and epigenetic marks will be analyzed. The extent of pelvic pain coincident with prostate inflammation in the mouse model will also be ascertained. In parallel, human patient material from open prostatectomy and radical prostatectomy cases with inflammation will be characterized. Patterns of gene expression and DNA methylation in reactive and normal epithelia will be quantified in samples from patients with and without lower urinary tract symptoms. These analyses will provide new insights into the effects of inflammation on the transcriptome and eipgenome of human prostate epithelial cells, which can be capitalized upon both diagnostically and therapeutically in future studies to alleviate the morbidity associated with benign prostatic disease and its coincident voiding syndromes. PUBLIC HEALTH RELEVANCE: The proposed work is directly relevant to human health because it will define changes in cells that occur in prostate diseases. There are existing classes of drugs that may be effective in counteracting these changes, and may therefore be effective in relieving lower urinary street symptoms that commonly occur in benign prostatic hyperplasia and prostatitis patients.