Erectile dysfunction (ED) affects 52% of men between the ages of 40 and 70. 30-87% of prostate cancer patients treated by prostatectomy experience ED and PDE5 inhibitors are ineffective in 29-86% of prostatectomy patients who experience ED, depending on their nerve injury status. The reduced efficacy of treatments in this population makes novel therapeutic approaches to treat ED essential. Significantly increased apoptosis of penile smooth muscle is common in both animal models and human patients with ED. We propose that abundant apoptosis observed in penile smooth muscle when the CN is cut is a major contributing factor to ED development. If apoptosis could be prevented following prostatectomy while the CN regenerates, then resumption of normal erectile function would occur more quickly, and irreversible morphology changes in the penis that cause ED would be prevented. Understanding the mechanisms that regulate smooth muscle apoptosis in the penis is critical for development of new therapeutic approaches for ED treatment and prevention. Sonic hedgehog (SHH) is an essential regulator of penile smooth muscle. When SHH is inhibited in the penis, there is a 12-fold increase in smooth muscle apoptosis that results in ED. SHH protein treatment is able to suppress CN injury induced apoptosis, indicating that SHH has significant potential to be developed as a treatment to prevent ED by suppressing smooth muscle apoptosis. The Affi-Gel bead technology used in these studies is not applicable to humans, so we propose to develop nanoparticle delivery of SHH protein to the penis and hypothesize that SHH delivery via nanoparticles will be effective in suppressing apoptosis induction caused by CN injury. This novel technology has substantial potential to be developed into a therapy to prevent apoptosis in patients at the time of prostatectomy, so has significant clinical relevance. The mechanism of how SHH itself is regulated in the penis and how decreased SHH protein induces apoptosis is poorly understood. It is likely that neural input/integrity regulates SHH in the penis since SHH protein is significantly decreased in two models of neuropathy, the CN injured rat and in the BB/WOR diabetic rat. Since SHH protein is decreased in diabetic human penes in parallel with observations in the rat, this lends clinical significance to how decreased SHH protein can induce apoptosis in the penis. Our results suggest that HIP out competes PTCH1 for SHH binding after CN injury. Thus we hypothesize that loss of neural input decreases SHH protein in the penis and induces apoptosis in penile smooth muscle through a PTCH1 and HIP dependent mechanism.

Public Health Relevance

Erectile dysfunction (ED) is a significant medical condition and current treatment options are ineffective in diabetic patients and in prostate cancer patients treated by prostatectomy. Sonic hedgehog (SHH) is an essential regulator of penile smooth muscle that has significant potential to be developed as a treatment to prevent ED by suppressing smooth muscle apoptosis. We propose to develop nanoparticle delivery of SHH protein as a therapy to prevent apoptosis in patients at the time of prostatectomy. The mechanism of how SHH itself is regulated in the penis and how decreased SHH protein induces apoptosis is poorly understood and will be examined in depth in this proposal.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK079184-04
Application #
8239900
Study Section
Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
Program Officer
Hoshizaki, Deborah K
Project Start
2009-03-19
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2012
Total Cost
$322,587
Indirect Cost
$104,949
Name
Northwestern University at Chicago
Department
Urology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Angeloni, Nicholas L; Bond, Christopher W; McVary, Kevin T et al. (2013) Sonic hedgehog protein is decreased and penile morphology is altered in prostatectomy and diabetic patients. PLoS One 8:e70985
Bond, Christopher W; Angeloni, Nicholas; Harrington, Daniel et al. (2013) Sonic Hedgehog regulates brain-derived neurotrophic factor in normal and regenerating cavernous nerves. J Sex Med 10:730-7
Podlasek, Carol A; Ghosh, Rudrani; Onur Cakir, Omer et al. (2013) Nerve growth factor signaling following unilateral pelvic ganglionectomy in the rat ventral prostate is age dependent. Asian J Androl 15:764-9
Angeloni, Nicholas L; Bond, Christopher W; Tang, Yi et al. (2011) Regeneration of the cavernous nerve by Sonic hedgehog using aligned peptide amphiphile nanofibers. Biomaterials 32:1091-101
Bond, Christopher W; Angeloni, Nicholas L; Harrington, Daniel A et al. (2011) Peptide amphiphile nanofiber delivery of sonic hedgehog protein to reduce smooth muscle apoptosis in the penis after cavernous nerve resection. J Sex Med 8:78-89
Bond, Christopher W; Angeloni, Nicholas L; Podlasek, Carol A (2010) Analysis of testosterone effects on sonic hedgehog signaling in juvenile, adolescent and adult sprague dawley rat penis. J Sex Med 7:1116-25
Angeloni, Nicholas L; Bond, Christopher W; Monsivais, Diana et al. (2009) The role of hedgehog-interacting protein in maintaining cavernous nerve integrity and adult penile morphology. J Sex Med 6:2480-93
Podlasek, Carol A (2009) Sonic hedgehog, apoptosis, and the penis. J Sex Med 6 Suppl 3:334-9