Role of DNA methylation in prostate glandular development and urinary function

描述(由申请人提供)：尿路功能是如何获得的，以及为什么老年男性的尿路功能恶化导致下尿路症状(LUTS)尚不清楚。我们令人信服的新的初步结果最终证明，从怀孕到成年，DNA甲基化塑造了尿路功能。我们提供的证据表明，DNA甲基化通过控制胎儿前列腺腺的发育来建立成人排尿行为。我们发现它通过一种平行的机制维持成人的排尿行为。最重要的是，我们发现它可以靶向预防排尿功能障碍。一种药理DNA甲基化增强剂，当给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，这是有梗阻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的反应，控制腺的生长并影响尿流。我们称这一假说为雄激素作用的表观遗传增强(EEAA)。具体目标将决定是否：(1)胎儿前列腺DNA甲基化建立成人尿路功能，(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甲基化预防尿路功能障碍。总体目标是在前列腺DNA甲基化和泌尿生理之间建立新的机制联系，以确定尿路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.