Reduced Levels of 5-alpha Reductase 2 in Adult Prostate Tissue and BPH Therapy

成人前列腺组织中 5-α 还原酶 2 水平的降低和 BPH 治疗

基本信息

批准号：
8528577
负责人：
Aria F Olumi
金额：
$ 36.73万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-15 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8528577
关键词：
Accounting Adrenergic alpha-Antagonists Adult Affect American Androgens Apoptosis Benign Benign Prostatic Hypertrophy Bladder Cell Line Chemoprevention Chronic Clinical Research Complication CpG Islands CpG dinucleotide Disease Disease Progression Elderly man Enzymes Epithelial Epithelial Cells Expenditure Finasteride Gene Expression Gene Expression Regulation Gene Silencing Genes Growth Growth and Development function Hair follicle structure Healthcare Human Island Lead Magnetic Resonance Imaging Malignant neoplasm of prostate Medical Methylation Obstruction Office Visits Operative Surgical Procedures Oxidoreductase Patient observation Patients Pattern Pelvis Pharmaceutical Preparations Promoter Regions Prostate Prostatic Proteins Repression Research Resistance Risk Sampling Secondary to Skin Smooth Muscle Myocytes Specimen Stanolone Strategic Planning Stromal Cells Symptoms Testosterone Testosterone 5-alpha-Reductase Therapeutic Tissues United States National Institutes of Health Urethra age related base cholestenone 5 alpha-reductase design improved inhibitor/antagonist lower urinary tract symptoms men promoter prostate transurethral resection protein expression resistance mechanism therapy resistant treatment strategy urinary tract obstruction

项目摘要

DESCRIPTION (provided by applicant): 5-1 reductase 2 inhibitors are commonly used for medical management of patients with obstructive uropathy secondary to benign prostatic hyperplasia (BPH). Finasteride, the most commonly used 5-1 reductase inhibitor, is prescribed to 8.2 million American men. Based on our preliminary results, we estimate that 2.37 million of those men are resistant to its therapeutic action, because they do not express its intended target enzyme, 5-1 reductase 2, accounting for $640 million in annual health care spending. Despite its common use, mechanisms accounting for resistance to Finasteride are not understood. To explore why some patients are resistant to the widely used 5-1 reductase type 2 inhibitor, we evaluated the degree of expression of 5-1 reductase 2 in human prostate tissues. We found that there is a wide variability of expression of 5-1 reductase 2 in human prostate samples with 30% of different samples lacking expression of the protein. Since methylation of the CpG dinucleotide islands in the promoter region of genes has been associated with regulation of genes, we investigated whether the 5-1 reductase gene contains CpG islands. We found that the 5-1 reductase 2 promoters contains a rich CpG island and in fact the CpG island is methylated in many prostate cell lines which do not express 5-1 reductase 2. In addition, there is a strong correlation between methylation of 5-1 reductase 2 promoter regions and absence of 5-1 reductase 2 in human prostate samples. Therefore, we hypothesize that methylation of the promoter region of 5-1 reductase 2 gene is associated with reduced expression of the protein, which can lead to stagnant or suppressed prostatic growth in adulthood, and possibly accounting for resistance to 5-1 reductase 2 inhibitor therapies. This clinical study is designed to explore the heterogeneous growth pattern of adult human prostates as related to expression of 5-1 reductase 2, and to evaluate the mechanisms of resistance to 5-1 reductase 2 inhibitions. The specific aims are: Specific Aim #1. To determine whether methylation of 5-1 reductase 2 promoter region is associated with repression of 5-1 reductase 2 protein in human prostate tissue. Specific Aim #2. To determine whether methylation of 5-1 reductase 2 promoter is associated with decreased prostatic growth rates. Specific Aim #3. To determine whether methylation of 5-1 reductase 2 promoter and reduced expression of 5-1 reductase 2 is associated with resistance to Finasteride in management of BPH. Our proposal is well-aligned with NIH/NIDDK's Prostate Research Strategic Plan. The findings will have broad implications for chronic use of 5-1 reductase 2 inhibitors for BPH, and also in newly suggested strategies for chemoprevention of prostate cancer. Recognition of mechanisms that regulate expression of 5-1 reductase 2 will lead to identification of newer compounds and better targeted therapies for BPH and reduce the rates of invasive therapies for this benign condition.

描述（由申请人提供）：5-1还原酶2抑制剂通常用于对继发于良性前列腺增生（BPH）继发的阻塞性尿症患者的医疗管理。非那雄胺是最常用的5-1还原酶抑制剂，规定了820万美国男性。根据我们的初步结果，我们估计有237万人对其治疗行动有抵抗力，因为他们没有表达其预期的目标酶，即5-1还原酶2，占年度医疗保健支出的6.4亿美元。尽管使用了普遍的使用，但尚不清楚考虑到对非那雄胺的抗性的机制。为了探索为什么某些患者对广泛使用的5-1还原酶2型抑制剂具有抗性，我们评估了人类前列腺组织中5-1还原酶2的表达程度。我们发现，在人类前列腺样品中，5-1还原酶2的表达差异很大，其中30％的不同样品缺乏蛋白质表达。由于基因启动子区域中CpG二核苷酸岛的甲基化与基因的调节有关，因此我们研究了5-1还原酶基因是否含有CpG岛。我们发现，5-1还原酶2启动子含有丰富的CpG岛，实际上CpG岛是在许多前列腺细胞系中甲基化的，这些细胞系未表达5-1还原酶2。此外，5-1还原酶2启动子区域的甲基化和5-1个还原酶2在人类前列腺样品中的甲基化之间存在很强的相关性。因此，我们假设5-1还原酶2基因的启动子区域的甲基化与蛋白质的表达降低有关，蛋白质的表达降低，这可能导致成年期停滞或抑制的前列腺生长，并可能考虑到5-1还原酶2还原酶2抑制剂疗法。这项临床研究旨在探索与5-1还原酶2的表达相关的成年人前列腺的异质生长模式，并评估对5-1还原酶2抑制的抗性机制。具体目的是：特定目标＃1。确定5-1还原酶2启动子区域的甲基化是否与人类前列腺组织中5-1还原酶2蛋白的抑制有关。特定目标＃2。确定5-1还原酶2启动子的甲基化是否与前列腺生长速率降低有关。特定目标＃3。为了确定5-1还原酶2启动子的甲基化和5-1还原酶2的表达是否与BPH管理中对非那雄胺的抗性有关。我们的建议与NIH/NIDDK的前列腺研究战略计划非常合适。这些发现将对5-1还原酶2抑制剂的长期使用对BPH有广泛的影响，并且在新建议的预防前列腺癌的策略中也具有广泛的影响。识别调节5-1还原酶2表达的机制，将导致鉴定出较新的化合物和BPH的靶向疗法更好，并降低这种良性条件的侵入性疗法率。