Role of Inflammation and Epigenetics in Benign Prostate Pathology

炎症和表观遗传学在良性前列腺病理学中的作用

• 批准号: 8150964
• 负责人: CHARLES J. BIEBERICH
• 金额: $ 31.05万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE COUNTY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8150964
• 关键词: Benign; Benign Prostatic Hypertrophy; Cells; Clinical Research; DNA Methylation; Differentiation and Growth; Drug Delivery Systems; Epigenetic Process; Epithelial Cells; Epithelium; Etiology; Event; Future; Gene Expression; Gene Expression Profile; Goals; Health; Human; Inflammation; Inflammatory; Inflammatory Response; Life; Long-Term Effects; Mediating; Mediator of activation protein; Morbidity - disease rate; Morphology; Pathology; Patients; Pattern; Pelvic Pain; Pharmaceutical Preparations; Prostate; Prostatectomy; Prostatic Diseases; Quality of life; Radical Prostatectomy; Role; Sampling; Stromal Cells; Symptoms; Syndrome; Transgenic Mice; Translating; Urinary tract; Work; cytokine; insight; lower urinary tract symptoms; mouse model; novel therapeutics; prostatitis; public health relevance; urinary

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.

描述（由申请人提供）：与良性前列腺增生和前列腺炎有关的较低尿路症状对生活质量产生了深远的影响。与良性前列腺疾病共同发生的尿路排尿综合征尤其令人困扰，在极端情况下，可能会威胁生命。这里提出的工作的总体目标是定义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。进行这项研究的理由是，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的表观遗传变化介导的，而表观基因组目前是可访问的药物靶标。因此，通过成功完成此处提议的工作来确认这一假设，将通过告知现有药物的新治疗应用来迅速转化为患者福利。来自临床研究的证据强烈暗示细胞因子在良性前列腺疾病的病因中的异常表达。众所周知，细胞因子是炎症反应的主要介体，但也可以直接影响上皮细胞和基质细胞。为了确定前列腺中促炎性细胞因子表达增加的后果，将开发和表征有条件的转基因小鼠模型。上调ILI 7和ILI P对前列腺炎症，形态，基因表达和表观遗传标记的影响。还将确定骨盆疼痛与小鼠模型中的前列腺炎症一致的程度。同时，将表征来自开放式前列腺切除术和炎症的根治性前列腺切除术病例的人类患者材料。反应性和正常上皮中的基因表达和DNA甲基化模式将在有和没有尿路症状较低的患者的样品中进行量化。这些分析将为炎症对人前列腺上皮细胞的转录组和EIPGENOME的影响提供新的见解，这些细胞可以在未来的研究中对诊断和治疗中的利用，以减轻与良性前列腺疾病及其一致依次的依从性综合症相关的发病率。 公共卫生相关性：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。现有的药物可能有效抵消这些变化，因此可以有效缓解较低的尿路症状症状，这些疾病通常发生在良性的前列腺增生和前列腺炎患者中。