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.
Most aging men will develop LUTS with advanced age and many will require treatment. Factors that impact androgen action have a clear role in prostate gland growth and obstructive LUTS. Our preliminary results represent the discovery of an entirely new link between prostate DNA methylation and androgen responsiveness, glandular growth, and urinary dysfunction. Not only does the proposed research have a high likelihood of providing new knowledge of how urinary dysfunction arises, it also has a very high probability of discovering new therapies for preventing or treating an underlying cause of LUTS.
|Keil, Kimberly P; Abler, Lisa L; Laporta, Jimena et al. (2014) Androgen receptor DNA methylation regulates the timing and androgen sensitivity of mouse prostate ductal development. Dev Biol 396:237-45|
|Laporta, Jimena; Keil, Kimberly P; Weaver, Samantha R et al. (2014) Serotonin regulates calcium homeostasis in lactation by epigenetic activation of hedgehog signaling. Mol Endocrinol 28:1866-74|
|Keil, Kimberly P; Abler, Lisa L; Altmann, Helene M et al. (2014) Influence of animal husbandry practices on void spot assay outcomes in C57BL/6J male mice. Neurourol Urodyn :|