Role of Inflammation and Epigenetics in Benign Prostate Pathology

描述（由申请人提供）：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影响。与良性前列腺疾病同时发生的尿路排尿综合征特别令人烦恼，在极端情况下，可能危及生命。本文提出的工作的总体目标是确定炎症在良性前列腺病理学中的作用，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。进行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变化介导的，并且表观基因组是目前可获得的药物靶点。因此，通过成功完成本文提出的工作来证实这一假设，将通过告知现有药物的新治疗应用而迅速转化为患者受益。来自临床研究的证据强烈暗示细胞因子的异常表达在良性前列腺疾病的病因学中。众所周知，细胞因子是炎症反应的主要介质，但也可对上皮细胞和基质细胞具有直接作用。为了确定前列腺中促炎细胞因子表达增加的后果，将开发和表征条件性转基因小鼠模型。将分析上调的ILI 7和ILI p对前列腺炎症、形态学、基因表达和表观遗传标记的影响。还将确定小鼠模型中与前列腺炎症同时发生的盆腔疼痛的程度。同时，将表征来自具有炎症的开放性直肠癌切除术和根治性直肠癌切除术病例的人类患者材料。将在有和无下尿路症状的患者样本中定量反应性和正常上皮细胞中的基因表达和DNA甲基化模式。这些分析将为炎症对人前列腺上皮细胞转录组和eipgenome的影响提供新的见解，这可以在未来的研究中用于诊断和治疗，以减轻与良性前列腺疾病及其并发排尿综合征相关的发病率。 公共卫生相关性：这项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和前列腺炎患者中常见的下泌尿道症状。

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.