Erectile dysfunction (ED) affects ~ 50% of men aged 40 to 70 and has a high impact on men's health and quality of life. Current treatments are ineffective in the difficult to treat prostatectomy (16-82%) and diabetic (56-59%) patients due to injury to the cavernous nerve (CN), which provides innervation to the penis. With denervation the critical smooth muscle (SM) undergoes apoptosis and the penis becomes fibrotic, with increased collagen abundance and a change in subtypes, thus altering the architecture of the corpora cavernosa. This application is significant because we propose a novel integrative approach that targets the 3 main morphological changes that underlie ED, which are CN degeneration, SM apoptosis, and penile fibrosis. We've shown that sonic hedgehog (SHH) is a critical regulator of SM apoptosis in the penis and of CN regeneration. SHH pathway is of high interest as a candidate ED therapy because SHH regulates a critical nexus of pathways required to maintain erectile function. Our data in prostatectomy and diabetic patients shows altered morphology and decreased SHH protein in high fidelity to our rat ED model. In the rat SHH inhibition causes demyelination and axonal degeneration of CN fibers and CN crush decreases SHH protein 70% in the CN. SHH inhibition in the penis causes SM apoptosis and ED while CN crush decreases penile SHH. We show reversible penile remodeling with reestablishment of SHH signaling using two innovative peptide amphiphile (PA) delivery prototypes. In a crush model, SHH treatment of the CN (PA1) and of the penis (PA2) accelerates regeneration, improves erectile function >60%, suppresses apoptosis and preserves penile SM 56%. We will extend our observations to improve effectiveness of SHH delivery for maximal apoptosis suppression and CN regeneration in preparation for clinical translation (Aim 1), and design PAs that bind to SHH to fine tune release kinetics and duration in vivo in the penis (Aim 2). SHH PAs will be examined in an aged prostatectomy model that better simulates ED patient conditions (Aim 3). SHH PA is highly translatable for treatment of prostatectomy and diabetic patients by substituting human SHH protein for rat. SM apoptosis (2-7 days) occurs before increased collagen (7-14 days) in prostatectomy patients. We propose the innovative hypothesis that suppressing SM apoptosis can prevent the fibrotic response (Aim 4). Increased collagen is common in ED patients following prostatectomy. We show collagen abundance is responsive to SHH signaling (SHH inhibition increases collagen/SHH treatment decreases collagen), by an unknown mechanism. Microarray of corpora cavernosa from ED patients shows increased Gremlin 1, a BMP4 antagonist. SHH is a regulator of Gremlin in limb bud, Gremlin regulates fibrosis in lung, and BMP4 is inversely responsive to SHH during development. We hypothesize that reduced SHH that occurs in the penis with CN injury, up-regulates BMP4 leading to fibrosis (Aim 4). Understanding where intervention in the penile remodeling process will be effective to prevent ED is critical for development of novel therapies.

Public Health Relevance

We propose a novel integrative approach that targets the 3 main morphological changes that underlie erectile dysfunction (ED), which are cavernous nerve (CN) degeneration, smooth muscle apoptosis, and penile fibrosis. This application is innovative because we are developing two novel peptide amphiphile nanofiber hydrogels for delivery of sonic hedgehog (SHH) protein to the CN and to the penis to promote regeneration and prevent penile apoptosis. These studies will have broad clinical application and impact since SHH nanofibers can be used to regenerate any peripheral nerve that SHH plays a role in maintaining nerve integrity including the CN, sciatic and facial nerves and because the SHH nanofibers are highly translatable for treatment of ED in prostatectomy and diabetic patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK101536-06
Application #
9739592
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kirkali, Ziya
Project Start
2014-09-01
Project End
2024-06-30
Budget Start
2019-09-01
Budget End
2020-06-30
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Urology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Hehemann, Marah; Kalmanek, Elizabeth; Choe, Shawn et al. (2018) Sonic hedgehog regulation of human rhabdosphincter muscle:Potential implications for treatment of stress urinary incontinence. Neurourol Urodyn 37:2551-2559
Dobbs, Ryan; Kalmanek, Elizabeth; Choe, Shawn et al. (2018) Sonic hedgehog regulation of cavernous nerve regeneration and neurite formation in aged pelvic plexus. Exp Neurol 312:10-19
Hehemann, Marah; Choe, Shawn; Kalmanek, Elizabeth et al. (2018) Pelvic and hypogastric nerves are injured in a rat prostatectomy model, contributing to development of stress urinary incontinence. Sci Rep 8:16432
Dobbs, Ryan; Choe, Shawn; Kalmanek, Elizabeth et al. (2018) Peptide amphiphile delivery of sonic hedgehog protein promotes neurite formation in penile projecting neurons. Nanomedicine 14:2087-2094
Choe, Shawn; Bond, Christopher W; Harrington, Daniel A et al. (2017) Peptide amphiphile nanofiber hydrogel delivery of sonic hedgehog protein to the cavernous nerve to promote regeneration and prevent erectile dysfunction. Nanomedicine 13:95-101
Wang, Alice Y; Podlasek, Carol A (2017) Role of Nanotechnology in Erectile Dysfunction Treatment. J Sex Med 14:36-43
Podlasek, Carol A; Mulhall, John; Davies, Kelvin et al. (2016) Translational Perspective on the Role of Testosterone in Sexual Function and Dysfunction. J Sex Med 13:1183-98
Choe, Shawn; Veliceasa, Dorina; Bond, Christopher W et al. (2016) Sonic hedgehog delivery from self-assembled nanofiber hydrogels reduces the fibrotic response in models of erectile dysfunction. Acta Biomater 32:89-99
Musicki, Biljana; Bella, Anthony J; Bivalacqua, Trinity J et al. (2015) Basic Science Evidence for the Link Between Erectile Dysfunction and Cardiometabolic Dysfunction. J Sex Med 12:2233-55
Cakir, Omer Onur; Podlasek, Carol A; Wood, Douglas et al. (2015) Effect of Onabotulinum Toxin A on Substance P and Receptor Neurokinin 1 in the Rat Ventral Prostate. Andrology (Los Angel) 4: