Role of DNA methylation in prostate glandular development and urinary function

描述（由申请人提供）：尚不清楚泌尿功能是如何获得的，以及为什么老年男性的泌尿功能会恶化，从而导致下尿路症状（LUTS）。我们令人信服的新初步结果最终证明，从妊娠到成年，DNA甲基化塑造了泌尿功能。我们提供的证据表明，DNA甲基化通过控制胎儿前列腺腺体的发育来建立成人排尿行为。我们发现，它通过一个平行的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，当给予容易发生尿路梗阻的小鼠时，可以恢复DNA甲基化，防止不适当的腺体生长，并改善尿量，这是患有梗阻性排尿症状的男性的治疗目标。核心假设是从妊娠期到成年期，DNA甲基化控制雄激素受体表达，从而限制前列腺雄激素反应性，控制腺体生长并影响尿流出。我们将这一假说称为雄激素作用的表观遗传增强（EEAA）。具体目标将确定：（1）胎儿前列腺DNA甲基化是否建立成人泌尿功能，（2）成人前列腺DNA甲基化是否通过限制生长来维持适当的腺体密度，（3）成人前列腺DNA甲基化是否预防泌尿功能障碍。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。

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.