Role of DNA methylation in prostate glandular development and urinary function

DNA甲基化在前列腺发育和泌尿功能中的作用

• 批准号: 8891417
• 负责人: CHAD M. VEZINA
• 金额: $ 32.73万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8891417
• 关键词: Adult; Age; Aging; Androgen Receptor; Androgens; Behavior; Behavior Control; Beryllium; Clinical; DNA; DNA Methylation; Development; Diet; Elderly; Enhancers; Environment; Epigenetic Process; Fetal Development; Fetus; Folic Acid; Functional disorder; Gland; Goals; Growth; Healthcare; Hormones; Human; Knowledge; Link; Mus; Natural regeneration; Obstruction; Output; Pharmaceutical Preparations; Physiology; Play; Pregnancy; Probability; Prostate; Research; Resistance; Risk; Role; Shapes; Symptoms; Testing; Therapeutic; Urethra; Urinary Retention; Urine; Xenograft procedure; base; care burden; clinically significant; density; fetal; improved; lower urinary tract symptoms; men; minimally invasive; mouse model; new therapeutic target; prevent; public health relevance; receptor expression; urinary

DESCRIPTION (provided by applicant): How urinary function is acquired and why it deteriorates in aging men to cause lower urinary tract symptoms (LUTS) is not known. Our compelling new preliminary results conclusively demonstrate that from gestation through adulthood, DNA methylation shapes urinary function. We provide evidence that DNA methylation establishes adult voiding behavior by controlling prostate glandular development in the fetus. We show that it maintains adult voiding behavior through a parallel mechanism. Most importantly, we reveal that it can be targeted to prevent urinary dysfunction. A pharmacological DNA methylation enhancer, when given to mice prone to urinary obstruction, restores DNA methylation, prevents inappropriate gland growth, and improves urinary output, a therapeutic goal in men with obstructive voiding symptoms. The central hypothesis is that from gestation to adulthood, DNA methylation controls androgen receptor expression to restrict prostate androgen responsiveness, control glandular growth and influence urinary outflow. We term this hypothesis Epigenetic Enhancement of Androgen Action (EEAA). Specific aims will determine whether: (1) Fetal prostate DNA methylation establishes adult urinary function, (2) Adult prostate DNA methylation maintains appropriate gland density by restricting growth, (3) Adult prostate DNA methylation prevents urinary dysfunction. The overarching goal is to establish a new mechanistic connection between prostate DNA methylation and urinary physiology that identifies an underlying basis of urinary function and a new therapeutic target for treating LUTS.

描述（由申请人提供）： 排尿功能如何获得以及为何排尿功能在老年男性中恶化并导致下尿路症状（LUTS）尚不清楚。我们令人信服的新初步结果最终证明，从妊娠到成年，DNA 甲基化塑造泌尿功能。我们提供的证据表明，DNA 甲基化通过控制胎儿前列腺发育来建立成人排尿行为。我们证明它通过并行机制维持成人排尿行为。最重要的是，我们发现它可以有针对性地预防泌尿功能障碍。一种药理学 DNA 甲基化增强剂，当给予易出现尿路梗阻的小鼠时，可以恢复 DNA 甲基化，防止腺体不适当生长，并改善尿量，这是患有梗阻性排尿症状的男性的治疗目标。核心假设是，从妊娠到成年，DNA 甲基化控制雄激素受体的表达，从而限制前列腺雄激素反应、控制腺体生长并影响尿液流出。我们将这种假说称为雄激素作用的表观遗传增强（EEAA）。具体目标将确定是否：(1) 胎儿前列腺 DNA 甲基化建立成人泌尿功能，(2) 成人前列腺 DNA 甲基化通过限制生长维持适当的腺体密度，(3) 成人前列腺 DNA 甲基化预防泌尿功能障碍。总体目标是在前列腺 DNA 甲基化和泌尿生理学之间建立新的机制联系，确定泌尿功能的潜在基础和治疗 LUTS 的新治疗靶点。